CN117903154A - Preparation method of 1-oxo-6-azaspiro [3.3] heptane-6-carboxylic acid tert-butyl ester - Google Patents
Preparation method of 1-oxo-6-azaspiro [3.3] heptane-6-carboxylic acid tert-butyl ester Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims description 9
- HUDZBXKDAQRXNO-UHFFFAOYSA-N tert-butyl 7-oxo-2-azaspiro[3.3]heptane-2-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC11C(=O)CC1 HUDZBXKDAQRXNO-UHFFFAOYSA-N 0.000 title abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 82
- 238000006243 chemical reaction Methods 0.000 claims abstract description 42
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical group CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims abstract description 20
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims abstract description 14
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229910052700 potassium Inorganic materials 0.000 claims abstract description 7
- 239000011591 potassium Substances 0.000 claims abstract description 7
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 claims abstract description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 14
- 239000003513 alkali Substances 0.000 claims description 14
- 239000003153 chemical reaction reagent Substances 0.000 claims description 13
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 12
- 230000003213 activating effect Effects 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 10
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 claims description 7
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 7
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- 230000003197 catalytic effect Effects 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 239000011630 iodine Substances 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 238000001308 synthesis method Methods 0.000 abstract description 5
- 239000012448 Lithium borohydride Substances 0.000 abstract description 3
- 238000011065 in-situ storage Methods 0.000 abstract 1
- 230000000269 nucleophilic effect Effects 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- 238000012216 screening Methods 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 235000019270 ammonium chloride Nutrition 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 5
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000012295 chemical reaction liquid Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000012467 final product Substances 0.000 description 4
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 102000001301 EGF receptor Human genes 0.000 description 2
- 108060006698 EGF receptor Proteins 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000007876 drug discovery Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 239000012450 pharmaceutical intermediate Substances 0.000 description 2
- 238000012827 research and development Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- -1 sulfoxide iodide Chemical class 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 238000006942 Corey-Chaykovsky ring formation reaction Methods 0.000 description 1
- 238000006680 Reformatsky reaction Methods 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 208000012839 conversion disease Diseases 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthesis method of 1-oxo-6-azaspiro [3.3] heptane-6-carboxylic acid tert-butyl ester, which takes 1-Boc-3-azacyclobutanone (formula II compound) as a starting material, and the 1-Boc-3-azacyclobutanone reacts with ethyl bromoacetate to generate a compound of formula III, and then potassium borohydride/lithium chloride in situ generates a lithium borohydride system for reduction, and then the lithium borohydride system is nucleophilic substituted with p-toluenesulfonyl chloride, and finally the finished product is prepared by closing the ring under alkaline condition, wherein the total yield of the four-step reaction reaches more than 50 percent.
Description
Technical field:
The invention relates to the field of synthesis of pharmaceutical intermediates, in particular to a preparation method of 1-oxo-6-azaspiro [3.3] heptane-6-carboxylic acid tert-butyl ester.
Background
1-Oxo-6-azaspiro [3.3] heptane-6-carboxylic acid tert-butyl ester is an important segment in drug design, its derivative has very high bioactivity, and Cortellis Drug Discovery Intelligence database search shows that a plurality of active substances containing the segment are in different stages of preclinical research; the derivatives can be used for drug research of targets such as bispecific protein kinase TTK (MPS 1; MPS1L 1) (US 2014005167A), epidermal Growth Factor Receptor (EGFR) (WO 2013091507A 1) and the like. In recent years, the search for some active screening drugs by linking tert-butyl 1-oxo-6-azaspiro [3.3] heptane-6-carboxylate with specific structures has become one of the hot spots of research in the drug discovery stage. Thus, tert-butyl 1-oxo-6-azaspiro [3.3] heptane-6-carboxylate is a very promising pharmaceutical intermediate.
The synthesis method of the 1-oxo-6-azaspiro [3.3] heptane-6-carboxylic acid tert-butyl ester reported in the current literature is as follows: the compound of formula I (org. Lett.2010,12 (9): 1944-1947) is prepared from the compound of formula II by two Corey-Chaykovsky reaction processes:
the target product 1-oxo-6-azaspiro [3.3] heptane-6-carboxylic acid tert-butyl ester (formula I compound) is obtained by the one-step reaction, but excessive sulfur ylide reagent (trimethyl sulfoxide iodide) is used in the reaction, and the defects of high raw material price, severe heat release and difficult control in the reaction process, difficult purification in post-treatment and the like exist, so the process is not suitable for industrial production.
The 1-oxo-6-azaspiro [3.3] heptane-6-carboxylic acid tert-butyl ester (a compound shown as a formula I) is used as an active fragment to be applied to a plurality of new medicine research and development projects, and has larger market demands, so that a feasible synthetic route which is simple in research and development process, low in cost, easy to separate and purify and suitable for industrial production is required.
Disclosure of Invention
The invention aims to: in view of the above, the invention needs to provide a synthesis method of a drug intermediate 1-oxo-6-azaspiro [3.3] heptane-6-carboxylic acid tert-butyl ester, which has the advantages of simple process, convenient operation, high total yield, low requirements on equipment and environmental protection, and solves the technical problems of high synthesis cost and poor operability in the prior art.
The invention provides a preparation method of a compound shown in a formula I, which comprises the following steps:
(1) Step one: dissolving a compound of the formula II in an organic solvent, adding zinc powder and an activating reagent, heating and reacting for a period of time, and then adding ethyl bromoacetate to perform Raffin Ma Ciji reaction (Reformatsky) reaction to generate a compound of the formula III, wherein the activating reagent is selected from iodine or 1, 2-dibromoethane;
(2) Step two: dissolving potassium borohydride and lithium chloride in an organic solvent, reacting for a period of time, adding a compound of formula III, and reacting to generate a compound of formula IV;
(3) Step three: reacting a compound of the formula IV with p-toluenesulfonyl chloride under the action of alkali 1 to generate a compound of the formula V;
(4) Step four: the compound of formula V is reacted with base 2 to form the compound of formula I.
Preferably, in the step of preparing the compound of formula III from the compound of formula II, the activating reagent is 1, 2-dibromoethane;
Preferably, in the step of preparing the compound of formula III from the compound of formula II, the temperature of the reaction is in the range of 45-65 ℃;
preferably, the molar ratio of the compound of formula II, zinc powder and activating agent is in the range of 1:1.05-1.35:0.01-0.1;
preferably, in the step of preparing the compound of formula III from the compound of formula II, the molar ratio of the compound of formula II to the activating agent is in the range of 1:0.02-0.05;
Preferably, in the step of preparing the compound of formula IV from the compound of formula III, the molar ratio of the compound of formula III, potassium borohydride and lithium chloride is in the range of 1:1.5-2.5:1.5-2.5; the temperature range of the reaction is 50-60 ℃;
Preferably, in the step of preparing the compound of formula IV from the compound of formula V, base 1 is selected from triethylamine or N, N-diisopropylethylamine; the mol ratio of the compound of the formula IV, the tosyl chloride and the alkali 1 is 1:0.9-1:1.1-1.5; the temperature range of the reaction is-5-20 ℃.
Preferably, in the step of preparing the compound of formula V from the compound of formula IV, a catalytic amount of 4-dimethylaminopyridine is added to the reaction
Preferably, the step of preparing the compound of formula I from the compound of formula V, wherein the alkali 2 is selected from potassium tert-butoxide or sodium tert-butoxide, and the molar ratio of the compound of formula V to the alkali 2 is 1:1.05-1.2;
preferably, a step of preparing the compound of formula I from the compound of formula V, wherein the compound of formula V is dissolved in an organic solvent, then the base 2 is added in batches, and the temperature is kept at-10-5 ℃ when the base 2 is added; the reaction temperature range after the addition of the alkali 2 is 5-20 ℃.
Advantageous effects
The first step Reformatsky reaction of the synthetic route disclosed by the invention has the advantages that the yield of the first step reaction reaches more than 90% by optimizing the reagent, the reaction temperature and the reagent equivalent ratio of the activated zinc powder; the synthesis method of the compound with the similar structure reported in the literature combines three steps and four steps into one step reaction, shortens the reaction route, but after the reaction is finished, the post-treatment is complicated because the system is relatively miscellaneous, and the compound with the formula I of the final product can be obtained by column chromatography purification; the invention is reacted with p-toluenesulfonyl chloride in two steps, and then treated to obtain a pure compound of formula V, and then the compound of formula I can be conveniently purified to obtain a high-purity final product through a ring-closing reaction, so that the purity of the product can reach more than 98%. In conclusion, compared with the one-step synthesis method reported in the prior literature, the method provided by the invention has the advantages of cheap reagent raw materials, convenience in operation, easiness in product purification, suitability for technological production and the like.
The abbreviations of the partial reactants involved in the present invention are as follows:
TEA: triethylamine
DIPEA: n, N-diisopropylethylamine
MTBE: methyl tert-butyl ether
DMAP: 4-dimethylaminopyridine
LAH: lithium aluminum hydride
THF: tetrahydrofuran (THF)
DMF: n, N-dimethylformamide
Drawings
For a clearer description of embodiments of the invention or of solutions according to the prior art, the drawings that are used in the description of the embodiments or of the prior art will be briefly described, it being apparent that the drawings in the description that follow are some embodiments of the invention.
FIG. 1 is a 1 H-NMR spectrum of the final product of example 1 according to the invention;
FIG. 2 is a GC spectrum of the final product of example 1 of the invention.
Detailed Description
The invention will be further illustrated by the following examples, which are carried out on the basis of the technical solutions of the invention, and it should be understood that these examples are only intended to illustrate the invention and are not intended to limit the scope of the invention.
Example 1
Preparation of the compound of formula III:
The compound of formula II (7.5 kg,43.84mol,1 eq.) was dissolved in 45L THF, 1, 2-dibromoethane (0.284 kg, 4.284 mol,0.1 eq.) was added, and zinc powder (3.152 kg,48.22mol,1.1 eq.) was added with stirring, and the temperature was controlled at 55-65 ℃. The reaction was stirred for 1.5h and LC-MS detection showed that the reaction of 1, 2-dibromoethane was complete. Ethyl bromoacetate (8.053 kg,48.22,1.1 eq.) was added dropwise, the temperature being controlled at 45-55 ℃. After the dripping is finished, stirring and reacting for 2 hours at the temperature of 45-65 ℃. LC-MS shows that the raw materials are completely reacted, the temperature of the reaction solution is reduced to 20-30 ℃, and then 20% ammonium chloride aqueous solution is added into the reaction solution to quench the reaction. Stirring for 30-40min, dripping concentrated hydrochloric acid to adjust pH to 5-6, stirring, vacuum filtering, and removing residue. The reaction solution was concentrated under reduced pressure, the organic solvent was removed, ethyl acetate was added to extract the aqueous phase, the organic phases were combined, washed with a 20% aqueous ammonium chloride solution, and the organic phase was dried and concentrated to give 10.305kg of the compound of formula III in 90.7% yield.
Preparation of the compound of formula IV:
4.29kg of potassium borohydride and 3.371kg of anhydrous lithium chloride were dissolved in 80L of THF, and reacted at 30-50℃for 1-2 hours with stirring. A solution of compound III (10.305 kg,39.77mol,1 eq.) dissolved in 10L THF was added dropwise, the temperature was controlled to be not more than 50℃and the reaction was stirred at 40-50℃for 2-3h after the completion of the addition, and the reaction was complete as detected by LC-MS. Cooling the reaction liquid to 20-30 ℃, dropwise adding 20% ammonium chloride aqueous solution into the reaction liquid to quench the reaction, and stirring the reaction liquid for 8-12h after the addition. Suction filtration and THF washing of the filter cake. Standing for separating, concentrating the organic phase to remove the solvent, extracting the aqueous phase with ethyl acetate, mixing with the organic phase, cooling, adding 3.194kg of diluted hydrochloric acid dropwise, and stirring to react for 1-2h. A mixed aqueous solution of sodium hydrogencarbonate and sodium chloride was added dropwise, followed by stirring and then separation. The organic phase was concentrated to give 8.348kg of the compound of formula IV in 96.7% yield.
Preparation of the compound of formula V:
P-toluenesulfonyl chloride (6.60 kg,34.61mol,0.9 eq.) was dissolved in 150L THF for use. In a reaction vessel, the compound of formula IV (8.348 kg,38.45mol,1 eq.) was dissolved in 400L THF and triethylamine (4.279 kg,42.29mol,1.1 eq.) and 0.235kg DMAP were added at 0deg.C. After the addition, the THF solution of the p-toluenesulfonyl chloride is added dropwise at the temperature of-10 to-5 ℃, the reaction is stirred for 4 to 5 hours at the temperature of 10 to 20 ℃ after the addition, and LC-MS shows that the raw material reaction is complete. Adding water into the reaction solution to quench the reaction. After 0.8kg of concentrated hydrochloric acid is added dropwise at the temperature of-5-0 ℃, the reaction is stirred for 1-2h. Standing for separating, concentrating the organic phase, extracting the aqueous phase with ethyl acetate, and mixing the organic phases. A 20% aqueous ammonium chloride solution was added, and the aqueous phase was removed by separation after stirring. The organic phase was concentrated, recrystallised from MTBE and dried to give 12.6kg of the compound of formula V in 88.3% yield.
Preparation of the compound of formula I:
Compound V (10.09.612 kg,26.95mol,1 eq.) was dissolved in 360L MTBE and potassium tert-butoxide (3.62 kg,32.33mol,1.2 eq.) was added in portions at-10-0deg.C. After the addition, the reaction is carried out for 1 to 2 hours at-10 to 0 ℃ under the condition of heat preservation and stirring, and then the reaction is carried out for 4 hours at 20 ℃. LC-MS shows that the raw materials are completely reacted, 20% ammonium chloride aqueous solution is added into the reaction liquid at 10 ℃, the mixture is stirred for 30 to 40 minutes after the addition, the liquid is separated, the aqueous phase is extracted by MTBE, and the organic phases are combined. The organic phase was concentrated to no fraction, dissolved in n-heptane and ethyl acetate, suction filtered over silica gel (pre-wetted with n-heptane), rinsed with a mixture of n-heptane and ethyl acetate and combined. Concentrating under reduced pressure to remove solvent, distilling under reduced pressure with oil pump, and collecting 70 deg.C fraction to obtain compound of formula I4.043 kg with 75.3% yield.
1HNMR(400MHz,CDCl3)(ppm)：4.3993～4.3618(t,J＝7.52Hz,2H),4.0683～4.0432(d,J＝10.04Hz,2H),3.9297～3.9046(d,J＝10.04Hz,2H),2.8084～2.7709(t,J＝7.48Hz,2H),1.3700(s,9H);(ESI-TOF)m/z：[M+H]+calcd for C10H17NO3：199.25,found 200.35.GC The purity was 98.7%.
The screening test was conducted on the reaction conditions of each step by referring to the method of example 1, and the results are shown in tables 1 to 4.
TABLE 1 Experimental conditions screening at step one
The results show that in the first step, the compound of formula II is subjected to Raforol Ma Ciji reaction (Reformatsky) with ethyl bromoacetate, and the Zn powder after being activated by iodine or 1, 2-dibromoethane is used; the mol ratio of the compound of the formula II, zinc powder and the activating reagent is 1:1.05-1.35:0.01-0.1, and the compound of the formula III can be obtained with high yield under the condition of 45-65 ℃.
TABLE 2 Experimental conditions screening at step two
The result shows that in the second step, the compound of the formula III can be obtained with high yield under the condition of 50-60 ℃ by using the lithium borohydride prepared by the potassium borohydride/lithium chloride as a reducing agent.
Table 3 experimental condition screening in step three
The result shows that in the third step, the compound in the formula IV reacts with the p-toluenesulfonyl chloride, and the mol ratio of the compound in the formula IV, the p-toluenesulfonyl chloride and the alkali 1 is 1:0.9-1:1.1-1.5; adding catalytic amount of DMAP, and reacting at-5-20 ℃ to obtain the compound of formula IV with higher yield.
Table 4 experimental condition screening at step four
The result shows that in the fourth step, the compound of the formula V closes the ring under the alkaline condition, potassium tert-butoxide or sodium tert-butoxide is selected as alkali, and the temperature is kept at-10-5 ℃ when the alkali is added; the compound of the formula I can be obtained in higher yield under the condition that the reaction temperature is 5-20 ℃ after the alkali is added.
As can be seen from the comparison example, the preferred reaction conditions of the application are used for preparing the 1-oxo-6-azaspiro [3.3] heptane-6-carboxylic acid tert-butyl ester, the reaction conversion rate is higher, the impurity is less, the reaction conditions are mild, the operation is simple and convenient, and the method is suitable for industrial production.
Claims (10)
1.A process for the preparation of a compound of formula I comprising the steps of:
(1) Step one: dissolving a compound of the formula II in an organic solvent, adding zinc powder and an activating reagent, and adding ethyl bromoacetate to generate Raffin Ma Ciji reaction to generate a compound of the formula III, wherein the activating reagent is selected from iodine or 1, 2-dibromoethane;
(2) Step two: dissolving potassium borohydride and lithium chloride in an organic solvent, adding a compound of the formula III, and reacting to generate a compound of the formula IV;
(3) Step three: reacting a compound of the formula IV with p-toluenesulfonyl chloride under the action of alkali 1 to generate a compound of the formula V;
(4) Step four: the compound of formula V is reacted with base 2 to form the compound of formula I.
2. The method of manufacturing according to claim 1, characterized in that: in the step of preparing the compound of the formula III from the compound of the formula II, the activating reagent is 1, 2-dibromoethane, and the organic solvent is tetrahydrofuran.
3. The production method according to claim 1 or claim 2, characterized in that: in the step of preparing the compound of formula III from the compound of formula II, the temperature of the reaction is 45-65 ℃.
4. The method of manufacturing according to claim 1, characterized in that: in the step of preparing the compound of the formula II, the molar ratio of the compound of the formula II, zinc powder and an activating reagent is 1:1.05-1.35:0.01-0.1.
5. The method of manufacturing according to claim 1, characterized in that: in the step of preparing the compound of the formula II, the molar ratio of the compound of the formula II to the activating reagent is in the range of 1:0.02-0.05.
6. The method of manufacturing according to claim 1, characterized in that: in the step of preparing the compound of the formula III, the molar ratio of the compound of the formula III, potassium borohydride and lithium chloride is 1:1.5-2.5:1.5-2.5; the temperature of the reaction is 50-60 ℃.
7. The method of manufacturing according to claim 1, characterized in that: in the step of preparing the compound of formula V from the compound of formula IV, base 1 is selected from triethylamine or N, N-diisopropylethylamine; the mol ratio of the compound of the formula IV, the tosyl chloride and the alkali 1 is 1:0.9-1:1.1-1.5; the temperature range of the reaction is-5-20 ℃.
8. The production method according to claim 1 or claim 7, characterized in that: in the step of preparing the compound of formula V from the compound of formula IV, a catalytic amount of 4-dimethylaminopyridine is added to the reaction.
9. The method of manufacturing according to claim 1, characterized in that: and (3) preparing the compound shown in the formula V by using the compound shown in the formula I, wherein the alkali 2 is selected from potassium tert-butoxide or sodium tert-butoxide, and the molar ratio of the compound shown in the formula V to the alkali 2 is 1:1.05-1.2.
10. The production method according to claim 1 or claim 9, characterized in that: a step of preparing a compound of formula I from a compound of formula V, wherein after the compound of formula V is dissolved in an organic solvent, adding base 2 in batches, and keeping the temperature at-10-5 ℃ when adding the base 2; the reaction temperature range after the addition of the alkali 2 is 5-20 ℃.
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| CN202211248849.1A CN117903154A (en) | 2022-10-12 | 2022-10-12 | Preparation method of 1-oxo-6-azaspiro [3.3] heptane-6-carboxylic acid tert-butyl ester |
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| CN202211248849.1A CN117903154A (en) | 2022-10-12 | 2022-10-12 | Preparation method of 1-oxo-6-azaspiro [3.3] heptane-6-carboxylic acid tert-butyl ester |
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