CN114805176A - Preparation method of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane - Google Patents
Preparation method of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane Download PDFInfo
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- CN114805176A CN114805176A CN202210332264.1A CN202210332264A CN114805176A CN 114805176 A CN114805176 A CN 114805176A CN 202210332264 A CN202210332264 A CN 202210332264A CN 114805176 A CN114805176 A CN 114805176A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- BGOMFPZIMJCRDV-UHFFFAOYSA-N 6,6-dimethyl-3-azabicyclo[3.1.0]hexane Chemical compound C1NCC2C(C)(C)C21 BGOMFPZIMJCRDV-UHFFFAOYSA-N 0.000 title claims description 11
- 239000003960 organic solvent Substances 0.000 claims abstract description 38
- 238000006722 reduction reaction Methods 0.000 claims abstract description 29
- 150000001875 compounds Chemical class 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 23
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000011701 zinc Substances 0.000 claims abstract description 21
- 229910052725 zinc Inorganic materials 0.000 claims abstract description 21
- 239000002904 solvent Substances 0.000 claims description 44
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 39
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 34
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 229910052783 alkali metal Inorganic materials 0.000 claims description 21
- 150000001340 alkali metals Chemical class 0.000 claims description 21
- 238000002156 mixing Methods 0.000 claims description 20
- 239000000243 solution Substances 0.000 claims description 17
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 17
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 10
- 239000011259 mixed solution Substances 0.000 claims description 10
- 238000010992 reflux Methods 0.000 claims description 9
- 239000012046 mixed solvent Substances 0.000 claims description 8
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 8
- 239000012279 sodium borohydride Substances 0.000 claims description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- 239000003638 chemical reducing agent Substances 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- 239000000725 suspension Substances 0.000 claims description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000012448 Lithium borohydride Substances 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 239000011630 iodine Chemical group 0.000 claims description 2
- 229910052740 iodine Chemical group 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 125000001033 ether group Chemical group 0.000 claims 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 abstract description 13
- 238000004519 manufacturing process Methods 0.000 abstract description 8
- 238000009776 industrial production Methods 0.000 abstract description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 238000001816 cooling Methods 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 8
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 8
- 238000001914 filtration Methods 0.000 description 6
- -1 lithium aluminum hydride Chemical compound 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 4
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000012280 lithium aluminium hydride Substances 0.000 description 4
- 239000011592 zinc chloride Substances 0.000 description 4
- 235000005074 zinc chloride Nutrition 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 229960000517 boceprevir Drugs 0.000 description 2
- LHHCSNFAOIFYRV-DOVBMPENSA-N boceprevir Chemical compound O=C([C@@H]1[C@@H]2[C@@H](C2(C)C)CN1C(=O)[C@@H](NC(=O)NC(C)(C)C)C(C)(C)C)NC(C(=O)C(N)=O)CC1CCC1 LHHCSNFAOIFYRV-DOVBMPENSA-N 0.000 description 2
- 229910000085 borane Inorganic materials 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000002360 explosive Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000001502 supplementing effect Effects 0.000 description 2
- 208000005176 Hepatitis C Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 239000005456 alcohol based solvent Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000001427 coherent effect Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- NDOGLIPWGGRQCO-UHFFFAOYSA-N hexane-2,4-dione Chemical compound CCC(=O)CC(C)=O NDOGLIPWGGRQCO-UHFFFAOYSA-N 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
Abstract
The invention discloses a 6, 6-dimethyl-3-azabicyclo [3.1.0] shown as a formula TM]A process for the preparation of hexane comprising the steps of: in an organic solvent, under the action of zinc borohydride, a compound shown as a formula SM1 undergoes a reduction reaction shown as follows. The preparation method provided by the invention can reduce the production cost, improve the production safety and is more suitable for industrial production.
Description
Technical Field
The invention relates to a preparation method of an antiviral drug intermediate, in particular to a preparation method of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane.
Background
6, 6-dimethyl-3-azabicyclo [3.1.0] hexane, having the english name: 6, 6-Dimethyl-3-azabicyclo [3.1.0] hexane; CAS number: 943516-54-9, is an important intermediate for producing hepatitis C protease inhibitor Boceprevir (Boceprevir) and oral therapeutic drug PF-07321332, and has the following chemical structural formula:
in the preparation of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane, lithium aluminum hydride is mostly used as a reducing agent in the prior art, and 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2, 4-diketone is reduced to obtain a target product, such as the techniques disclosed in WO2007075790A1, WO2009073380A1 and the like.
WO2012049688A1 discloses a process for the preparation of 6, 6-dimethyl-3-azabicyclo- [3.1.0]Improved process for the production of-hexane and salts thereof using BF 3 -NaBH 4 Reduction system, reduction of 6, 6-dimethyl-3-azabicyclo [3.1.0]]Hexane-2, 4-dione gave the desired product, but BF 3 -NaBH 4 The reduction reaction of the reduction system is dangerous and has high requirements on production conditions.
In summary, the prior art preparation of 6, 6-dimethyl-3-azabicyclo [ 3.1.0%]The methods for preparing hexane mainly comprise the common use of expensive, flammable and explosive reducing reagent lithium aluminum tetrahydride, highly toxic and flammable borane and BF with larger reaction danger in the synthesis process 3 -NaBH 4 Therefore, there is still a need to develop more environmentally friendly and mild preparation methods.
Disclosure of Invention
The technical problem to be solved by the invention is to overcome the prior 6, 6-dimethyl-3-aza-bicyclo [3.1.0]]The reduction step in the preparation method of hexane needs to use flammable and explosive reducing reagent of lithium aluminum hydride, virulent and flammable borane and BF with larger reaction danger 3 -NaBH 4 And a 6, 6-dimethyl-3-azabicyclo [3.1.0] is provided]A method for preparing hexane is provided. The preparation method of the invention overcomes the problems existing in the prior art, can reduce the production cost and improve the production safety, and is more suitable for industrial production.
The invention provides a preparation method of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane shown as a formula TM, which comprises the following steps: in an organic solvent, under the action of zinc borohydride, carrying out reduction reaction on a compound shown as a formula SM1 as shown in the specification;
the organic solvent may be a solvent conventional in such reactions in the art, and in the present invention, preferably one or more of an ether-based solvent, an alcohol-based solvent and an aromatic hydrocarbon-based solvent. The ether solvent is preferably one or more of diethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, ethylene glycol dimethyl ether and 2-methyltetrahydrofuran, and more preferably tetrahydrofuran. The alcohol solvent is preferably one or more of methanol and ethanol, more preferably methanol. The aromatic hydrocarbon solvent is preferably one or more of benzene, toluene and xylene, more preferably toluene.
The organic solvent is more preferably an ether solvent, a mixed solvent of an ether solvent and an alcohol solvent, or a mixed solvent of an ether solvent and an aromatic hydrocarbon solvent. When the solvent is preferably a mixed solvent of an ether solvent and an alcohol solvent, the volume ratio of the ether solvent to the alcohol solvent is preferably 8: 3. When the solvent is preferably a mixed solvent of an ether solvent and an aromatic hydrocarbon solvent, the volume ratio of the ether solvent to the aromatic hydrocarbon solvent is preferably 1: 3.
The amount of the organic solvent is not limited to affect the reaction, and the volume-to-mass ratio of the organic solvent to the compound shown in formula SM1 is preferably 1 mL/g-50 mL/g, more preferably 10 mL/g-30 mL/g.
The molar ratio of the compound shown as the formula SM1 to the zinc borohydride can be a molar ratio conventionally used in such reactions in the field, and is preferably 1:3 to 1:8, and more preferably 1:3 to 1: 5.
The zinc borohydride can participate in the reaction in the form of zinc borohydride solid or zinc borohydride solution. The zinc borohydride can be prepared by adopting a preparation method which is conventional in the field, and the preparation method of the zinc borohydride preferably comprises the following steps: alkali metal borohydride and ZnX in an organic solvent 2 Mixing and reacting; wherein, X is chlorine, bromine or iodine. The organic solvent is the same as the organic solvent. The alkali metal borohydride is preferably lithium borohydride, sodium borohydride or potassium borohydride, more preferably sodium borohydride. The alkali metal borohydride and ZnX 2 The molar ratio of (a) to (b) is preferably 2: 1. The reaction temperature is preferably 0-25 ℃, and more preferably 0-10 ℃.
The temperature of the reduction reaction is not particularly limited, and is generally a reflux temperature of the organic solvent in the reaction solution at normal temperature and normal pressure. The temperature of the reduction reaction is preferably 70 to 110 ℃.
The time of the reduction reaction is not particularly limited, and is generally used as the end point of the reaction when the reaction does not proceed any more. The time of the reduction reaction is preferably 1 to 48 hours, more preferably 40 hours.
In one embodiment, the method for preparing 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane, as shown in formula TM, preferably comprises the following steps:
(1) mixing the alkali metal borohydride with the organic solvent to obtain a first mixed solution;
(2) mixing the first mixed solution with a compound shown as a formula SM1 to obtain a second mixed solution;
(3) adding ZnX into the second mixed solution in batches 2 While generating a reducing agent of zinc borohydride, carrying out the reduction reaction;
wherein the organic solvent and ZnX 2 Are as described above.
In the step (1), the volume-to-mass ratio of the organic solvent to the alkali metal borohydride is 1mL/g to 30mL/g, and preferably 3mL/g to 20 mL/g. The mixing temperature is preferably 0-25 ℃. Before the mixing, the temperature of the organic solvent is preferably controlled to be 0-10 ℃. Said mixing preferably comprises adding an alkali metal borohydride to said organic solvent.
In the step (2), the molar ratio of the compound represented by the formula SM1 to the alkali metal borohydride is preferably 1:1 to 1:10, and more preferably 1:4 to 1: 8. The mixing temperature is preferably 0-25 ℃. The mixing is preferably carried out by adding a compound shown as the formula SM1 into the first mixed solution.
In the step (3), the compound shown as the formula SM1 and ZnX 2 The molar ratio of (a) to (b) is preferably 1:1 to 1:8, more preferably 1:1 to 1: 4. The temperature of the reduction reaction is generally the reflux temperature of the organic solvent in the reaction solution at normal temperature and normal pressure. The temperature of the reduction reaction is preferably 70-110 ℃.
In another embodiment, the method for preparing 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane as shown in formula TM preferably comprises the following steps:
(a) reacting said organic solvent, said alkali metal borohydride and said ZnX 2 Mixing to obtain a suspension;
(b) heating the suspended matters in the step (a) to the reflux temperature of the organic solvent at normal temperature and normal pressure, mixing the suspended matters with a compound shown as a formula SM1, and carrying out the reduction reaction.
In step (a), the temperature of the mixing is preferably room temperature. Preferably, an alkali metal borohydride and ZnX are added to an organic solvent 2 。
After the reduction reaction is completed, a post-treatment step is preferably included. The method and conditions of the post-treatment step may be those of a post-treatment step conventional in the art, and preferably, the post-treatment step comprises the steps of: quenching the reaction solution of the reduction reaction, filtering, separating liquid, acidifying an organic phase with hydrochloric acid, distilling under vacuum to remove an organic solvent, adding water, extracting with DCM for three times, adjusting the pH of the aqueous phase to 11-13 with a sodium hydroxide solution, extracting with DCM for three times, drying the organic phase, and rectifying under reduced pressure.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
In the present invention, the normal temperature and pressure means room temperature (0 to 30 ℃) and one atmosphere pressure.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the preparation method provided by the invention can reduce the production cost, improves the production safety, and is more suitable for industrial production.
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 in the following examples, in which specific conditions are not specified, were selected according to conventional methods and conditions, or according to the commercial instructions.
The yield was calculated as follows:
example 1 (reduction with zinc borohydride and tetrahydrofuran):
adding tetrahydrofuran (500mL) into a 2L reactor, cooling to 10 ℃, then adding sodium borohydride (109g, 8eq), cooling to 0 ℃, dropwise adding a solution of SM1(50g, 1eq) in tetrahydrofuran (250mL), stirring for 10min, adding zinc chloride (196g, 4eq) in batches, supplementing tetrahydrofuran (350mL), refluxing for 40h, cooling the reaction solution to 0 ℃, slowly adding a 30% sodium hydroxide solution, keeping the temperature below 10 ℃, filtering, separating, acidifying the organic phase with hydrochloric acid, distilling under vacuum to remove the organic solvent, adding water, extracting with DCM for three times, adjusting the pH of the aqueous phase to 11-13 with the sodium hydroxide solution, extracting with DCM for three times, drying the organic phase, and rectifying under reduced pressure to obtain 38.56g of the target compound, wherein the yield is 96.7% and the purity is 99%.
The product structure is detected correctly by nuclear magnetic hydrogen spectrum and mass spectrum, and the detection result is as follows:
1 H NMR(CDCI3,400MHz)：3.01(m,2H),2.82(d,2H,J＝11.3Hz),1.67 (brs,1H),1.18(m,2H),0.94(s,3H),0.92(s,3H)；
MS theoretical value 112.19(M +1) + (ii) a Detection value of 112.25(M +1) + 。
Example 2 (reduction with zinc borohydride and methanol):
adding methanol (1000mL) into a 2L reactor, cooling to 0 ℃, then adding sodium borohydride (54.5g, 4eq), cooling to 0 ℃, adding SM1(50g, 1eq) in batches, stirring until no bubbles exist, adding zinc chloride (98g, 2eq) in batches, keeping the temperature at 0 ℃ and stirring for lh, refluxing for 40h, slowly adding water (500mL), slowly adding 30% sodium hydroxide aqueous solution, and keeping the temperature below 10 ℃; distilling under vacuum to remove organic solvent, filtering, leaching filter cake with dichloromethane, acidifying with hydrochloric acid, supplementing water, extracting with DCM for three times, adjusting pH of water phase to 11-13 with sodium hydroxide solution, extracting with DCM for three times, drying organic phase, and rectifying under reduced pressure to obtain target compound 36.8g, with yield 92.3% and purity 99%.
Example 3 (reduction using zinc borohydride, toluene and tetrahydrofuran as solvents):
to a 2L reactor were added tetrahydrofuran (250mL), toluene (750mL), sodium borohydride (109g, 8eq) and zinc chloride (196g, 4eq) and the resulting suspension was heated to reflux. The tetrahydrofuran is slowly distilled off, and the temperature is controlled at 90 +/-5 ℃ until a black solid is generated. A solution of SM1(50g, 1eq) in tetrahydrofuran (250mL) was added dropwise and refluxed at this temperature overnight. And (6) cooling. Slowly adding 30% sodium hydroxide aqueous solution, keeping the temperature below 10 ℃, filtering, separating liquid, acidifying an organic phase by hydrochloric acid, distilling under vacuum to remove an organic solvent, adding water, extracting by DCM for three times, adjusting the pH of an aqueous phase to 11-13 by the sodium hydroxide solution, extracting by DCM for three times, drying the organic phase, and rectifying under reduced pressure to obtain 37.7 g of a target compound, wherein the yield is 94.7%, and the purity is 99%.
Example 4 (reduction using zinc borohydride, methanol and tetrahydrofuran as solvents):
adding tetrahydrofuran (800mL), methanol (300mL) and sodium borohydride (109g, 8eq) into a 2L reactor, dropwise adding a solution of SM1(50g, 1eq) in tetrahydrofuran (250mL), adding zinc chloride (196g, 4eq) in portions at 0 ℃, stirring at 0 ℃ for 2h, then refluxing and stirring for 40h, cooling, slowly adding 30% sodium hydroxide aqueous solution to adjust the alkali, keeping the temperature below 10 ℃, filtering, separating, acidifying the organic phase with hydrochloric acid, distilling under vacuum to remove the organic solvent, adding water, extracting with DCM for three times, adjusting the pH of the aqueous phase to 11-13 with sodium hydroxide solution, extracting with DCM for three times, organically coherent, and performing reduced pressure distillation to obtain 37.3g of the target compound, wherein the yield is 93.6% and the purity is 99%.
Comparative example 1 (reduction using lithium aluminum hydride and tetrahydrofuran as solvents):
adding tetrahydrofuran (750mL) and lithium aluminum hydride (27.3g, 2eq) into a 2L reactor, cooling to 0 ℃, dropwise adding a solution of SM1(50g, 1eq) in tetrahydrofuran (250mL), stirring at 0 ℃ for 2h, then refluxing and stirring for 40h, cooling to 0 ℃, slowly adding water (27.3mL), adding a 15% sodium hydroxide solution (27.3mL), dropwise adding water (82mL), heating to room temperature, stirring for 15min, adding anhydrous magnesium sulfate, stirring for 15min, filtering, and rectifying the filtrate to obtain the target compound 32g, the yield is 80%, and the purity is 98%.
Claims (10)
1. A method for preparing 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane, as shown in formula TM, comprising the steps of: in an organic solvent, under the action of zinc borohydride, carrying out reduction reaction on a compound shown as a formula SM1 as shown in the specification;
2. the method of claim 1, wherein the method satisfies one or more of the following conditions:
(1) the organic solvent is one or more of an ether solvent, an alcohol solvent and an aromatic hydrocarbon solvent;
(2) the volume-mass ratio of the dosage of the organic solvent to the compound shown in the formula SM1 is 1 mL/g-50 mL/g;
(3) the molar ratio of the compound shown as the formula SM1 to the zinc borohydride is 1: 3-1: 8;
(4) the temperature of the reduction reaction is 70-110 ℃; and
(5) the time of the reduction reaction is 1-48 hours.
3. The method of claim 2, wherein the method satisfies one or more of the following conditions:
(1) the ether solvent is one or more of diethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, ethylene glycol dimethyl ether and 2-methyltetrahydrofuran;
(2) the alcohol solvent is one or more of methanol and ethanol;
(3) the aromatic hydrocarbon solvent is one or more of benzene, toluene and xylene;
(4) the volume-mass ratio of the dosage of the organic solvent to the compound shown in the formula SM1 is 10 mL/g-30 mL/g;
(5) the molar ratio of the compound shown as the formula SM1 to the zinc borohydride is 1: 3-1: 5; and
(6) the time of the reduction reaction is 40 hours.
4. The method according to claim 2, wherein the organic solvent is an ether solvent, a mixed solvent of an ether solvent and an alcohol solvent, or a mixed solvent of an ether solvent and an aromatic hydrocarbon solvent; when the solvent is a mixed solvent of an ether solvent and an alcohol solvent, the volume ratio of the ether solvent to the alcohol solvent is preferably 8: 3; when the solvent is a mixed solvent of an ether solvent and an aromatic hydrocarbon solvent, the volume ratio of the ether solvent to the aromatic hydrocarbon solvent is preferably 1: 3.
5. The preparation method according to claim 1, wherein the zinc borohydride takes part in the reaction in the form of a solid or a solution of zinc borohydride; the preparation method of the zinc borohydride preferably comprises the following steps: alkali metal borohydride and ZnX in an organic solvent 2 Mixing and reacting; wherein, X is chlorine, bromine or iodine.
6. The method according to claim 5, wherein the zinc borohydride is prepared by one or more of the following conditions:
(1) the alkali metal borohydride is lithium borohydride, sodium borohydride or potassium borohydride; preferably sodium borohydride;
(2) the alkali metal borohydride and ZnX 2 In a molar ratio of 2: 1; and
(3) the reaction temperature is 0-25 ℃, preferably 0-10 ℃.
7. The method of claim 1, comprising the steps of:
(1) mixing alkali metal borohydride with the organic solvent to obtain a first mixed solution;
(2) mixing the first mixed solution with a compound shown as a formula SM1 to obtain a second mixed solution;
(3) adding ZnX into the second mixed solution in batches 2 While generating a reducing agent of zinc borohydride, carrying out the reduction reaction;
wherein the organic solvent, alkali metal borohydride and ZnX 2 Are as described in any one of claims 1 to 6.
8. The method of claim 7, wherein the method satisfies one or more of the following conditions:
(1) in the step (1), the volume-to-mass ratio of the organic solvent to the alkali metal borohydride is 1 mL/g-30 mL/g, the mixing temperature is 0-25 ℃, and the alkali metal borohydride is added into the organic solvent in the mixing;
(2) in the step (2), the molar ratio of the compound shown as the formula SM1 to the alkali metal borohydride is 1: 1-1: 10, the mixing temperature is 0-25 ℃, and the compound shown as the formula SM1 is added into the first mixed solution;
(3) in the step (3), the compound shown as the formula SM1 and ZnX 2 The molar ratio of (A) to (B) is 1: 1-1: 8, and the temperature of the reduction reaction is 70-110 ℃.
9. The method of claim 8, wherein the method satisfies one or more of the following conditions:
(1) in the step (1), the volume-to-mass ratio of the organic solvent to the alkali metal borohydride is 3mL/g to 20 mL/g;
(2) in the step (2), the molar ratio of the compound shown as the formula SM1 to the alkali metal borohydride is 1: 4-1: 8;
(3) in the step (3), the compound shown as the formula SM1 and ZnX 2 The molar ratio of (a) to (b) is 1:1 to 1: 4.
10. The method of claim 1, comprising the steps of:
(a) mixing an organic solvent, an alkali metal borohydride and ZnX 2 Mixing to obtain a suspension;
(b) heating the suspended matters in the step (a) to the reflux temperature of the organic solvent at normal temperature and normal pressure, mixing the suspended matters with a compound shown as a formula SM1, and carrying out reduction reaction;
wherein the organic solvent, alkali metal borohydride and ZnX 2 Are as described in any one of claims 1 to 6.
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