CN114085176A - Synthesis method of 5-Boc-5-azaspiro [2.3] hexane-1-carboxylic acid - Google Patents
Synthesis method of 5-Boc-5-azaspiro [2.3] hexane-1-carboxylic acid Download PDFInfo
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- CN114085176A CN114085176A CN202111449510.3A CN202111449510A CN114085176A CN 114085176 A CN114085176 A CN 114085176A CN 202111449510 A CN202111449510 A CN 202111449510A CN 114085176 A CN114085176 A CN 114085176A
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- boc
- azaspiro
- hexane
- carboxylic acid
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- 238000001308 synthesis method Methods 0.000 title claims abstract description 9
- YHMUQYORLLKZHP-UHFFFAOYSA-N 5-[(2-methylpropan-2-yl)oxycarbonyl]-5-azaspiro[2.3]hexane-2-carboxylic acid Chemical compound C1N(C(=O)OC(C)(C)C)CC11C(C(O)=O)C1 YHMUQYORLLKZHP-UHFFFAOYSA-N 0.000 title claims description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000000243 solution Substances 0.000 claims abstract description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229940125904 compound 1 Drugs 0.000 claims abstract description 8
- 229940125782 compound 2 Drugs 0.000 claims abstract description 8
- 229940126214 compound 3 Drugs 0.000 claims abstract description 8
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 claims abstract description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims abstract description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims abstract description 6
- VMKIXWAFFVLJCK-UHFFFAOYSA-N tert-butyl 3-oxoazetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(=O)C1 VMKIXWAFFVLJCK-UHFFFAOYSA-N 0.000 claims abstract description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 5
- -1 sulfoxide iodide Chemical class 0.000 claims abstract description 5
- ALGKZVCWDZVMQN-UHFFFAOYSA-N 3-[(2-methylpropan-2-yl)oxycarbonyl]pentan-3-ylphosphonic acid Chemical compound CCC(CC)(P(O)(O)=O)C(=O)OC(C)(C)C ALGKZVCWDZVMQN-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000007864 aqueous solution Substances 0.000 claims abstract description 3
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 claims abstract 2
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 230000015572 biosynthetic process Effects 0.000 claims description 8
- 238000003786 synthesis reaction Methods 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 238000000926 separation method Methods 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 229930013930 alkaloid Natural products 0.000 description 2
- DSRNKUZOWRFQFO-UHFFFAOYSA-N cephalotaxine Natural products COC1=CC23CCCN2CCc4cc5OCOc5cc4C3=C1O DSRNKUZOWRFQFO-UHFFFAOYSA-N 0.000 description 2
- YMNCVRSYJBNGLD-KURKYZTESA-N cephalotaxine Chemical compound C([C@@]12C=C([C@H]([C@H]2C2=C3)O)OC)CCN1CCC2=CC1=C3OCO1 YMNCVRSYJBNGLD-KURKYZTESA-N 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 241000488899 Cephalotaxus Species 0.000 description 1
- 241000251555 Tunicata Species 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- HYFHYPWGAURHIV-UHFFFAOYSA-N homoharringtonine Natural products C1=C2CCN3CCCC43C=C(OC)C(OC(=O)C(O)(CCCC(C)(C)O)CC(=O)OC)C4C2=CC2=C1OCO2 HYFHYPWGAURHIV-UHFFFAOYSA-N 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- HYFHYPWGAURHIV-JFIAXGOJSA-N omacetaxine mepesuccinate Chemical compound C1=C2CCN3CCC[C@]43C=C(OC)[C@@H](OC(=O)[C@@](O)(CCCC(C)(C)O)CC(=O)OC)[C@H]4C2=CC2=C1OCO2 HYFHYPWGAURHIV-JFIAXGOJSA-N 0.000 description 1
- 229960002230 omacetaxine mepesuccinate Drugs 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 150000003413 spiro compounds Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- NFEGNISFSSLEGU-UHFFFAOYSA-N tert-butyl 2-diethoxyphosphorylacetate Chemical compound CCOP(=O)(OCC)CC(=O)OC(C)(C)C NFEGNISFSSLEGU-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/12—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention relates to a 5-Boc-5-azaspiro [2.3]]A synthesis method of hexane-1-carboxylic acid mainly solves the technical problems of unstable intermediate, troublesome separation, low yield and the like of the existing synthesis method. The synthesis method comprises the following steps: reacting diethyl phosphono acetic acid tert-butyl ester with sodium hydrogen in tetrahydrofuran solution, and adding 1-BOC-3-azetidinone to generate a compound 1; reacting the compound 1 with trimethyl sulfoxide iodide in dimethyl sulfoxide solution under the action of sodium hydrogen to generate a compound 2; reacting the compound 2 with trifluoroacetic acid in a dichloromethane solution to generate a compound 3; compound 3 in dioxane aqueous solution, and Boc2And O reacts to generate the target compound 4.
Description
Technical Field
The invention relates to a synthesis method of 5-Boc-5-azaspiro [2.3] hexane-1-carboxylic acid (cas: 1251012-82-4).
Background
The azaspiro structure is an important parent nucleus in a natural structure and widely exists in alkaloids in the nature, and the spiro compound often has important physiological activity and medicinal value due to the unique structure and properties. For example, cephalotaxine, is isolated from cephalotaxus and is the parent of the anticancer drugs cephalotaxine and homoharringtonine; the marine natural product cyclindrine A is a tricyclic alkaloid isolated from the sea squirt Clvaelina cyclindica.
The prior art is a method for synthesizing the compound disclosed in European Journal of Organic Chemistry (2021), the reaction formula is as follows:
the technical defects of the synthesis method are as follows: the generated intermediate 1 'is unstable and easy to hydrolyze under the reaction condition of the second step, so that the intermediate 2' cannot be generated through cyclization, and the crude product yield in the step is only 10%, and the overall yield is 6.5%. The 2 nd to 3 rd steps are separated and purified by a chromatographic column, the operation is troublesome, and the efficiency is low.
Disclosure of Invention
The invention aims to provide a synthesis method of 5-Boc-5-azaspiro [2.3] hexane-1-carboxylic acid, which mainly solves the technical problems of instability of an intermediate, troublesome separation, low yield and the like in the prior art.
The technical scheme of the invention is as follows: a method for synthesizing 5-Boc-5-azaspiro [2.3] hexane-1-carboxylic acid, comprising the steps of:
firstly, 1-BOC-3-azetidinone reacts with diethyl phosphono acetic acid tert-butyl ester in tetrahydrofuran solution under the action of sodium hydrogen, and then 1-BOC-3-azetidinone is added for reaction to generate a compound 1;
secondly, reacting the compound 1 with trimethyl sulfoxide iodide in dimethyl sulfoxide solution under the action of sodium hydrogen to generate a compound 2;
thirdly, reacting the compound 2 with trifluoroacetic acid in a dichloromethane solution at room temperature to generate a compound 3;
in the fourth step, compound 3 is reacted with Boc in dioxane aqueous solution under the action of sodium carbonate at room temperature2And O reacts to generate a target compound 4. The synthesis route is as follows:
firstly, reacting for 4 hours at 0 ℃; the second step is that the reaction temperature is 10 ℃ and the reaction time is 5 hours; the third step is reaction time of 2 hours; and in the fourth step, the volume ratio of dioxane to water is =1:2, and the reaction time is 2 hours.
The invention has the beneficial effects that: the synthesis circuit designed by the invention is an improvement on the basis of the prior art, and mainly has the following advantages:
1) the technical scheme is basically the same as the raw materials adopted by the prior art, the price difference is not large, the intermediate 1 'generated by the phosphoryl triethyl acetate adopted by the prior art is unstable and extremely easy to hydrolyze under the reaction condition of the second step, so that the intermediate 2' cannot be generated by cyclization, the yield of the crude product in the step is only 10%, and the overall yield is 6.5%. The intermediate 2 generated by the diethyl phosphono acetic acid tert-butyl ester adopted by the technical scheme is very stable, the yield is 87%, the overall yield is 43.1%, the yield is greatly improved, and the cost is reduced.
2) In the prior art, the 2 nd to 3 rd steps need to pass through a chromatographic column for separation and purification, the operation is troublesome, and the efficiency is low. In the technical scheme, crude products are obtained in each step and are directly put into the next step, and the pure products of the target products 4 can be obtained through crystallization. In addition, the prior art can only achieve gram level, and the technical scheme can realize kilogram level production and has practical value.
Drawings
FIG. 1 is a nuclear magnetic spectrum of the product of the present invention.
FIG. 2 is a chromatogram of a product of the present invention.
FIG. 3 is a mass spectrum of the product of the present invention.
Detailed Description
Example 1:
step 1:
tetrahydrofuran (1500 mL) was added to a 5-liter three-necked flask; sodium hydrogen (70 g, 1.75 mol) was added at 0 ℃; a solution of tert-butyl diethylphosphonoacetate (390 g, 1.546 mol) + tetrahydrofuran (500 mL) was added dropwise. After the addition of the mixture is finished and the mixture is stirred for 0.5 hour at 0 ℃, the solution of 1-BOC-3-azetidinone (220 g, 1.286 mol) + tetrahydrofuran (500 mL) is added into the reaction solution dropwise, and the mixture is stirred for 3.5 hours naturally to room temperature after the addition of the mixture, so that the system is clear.
The reaction was poured into ice water, extracted with ethyl acetate (500 mL × 2), the organic phase was separated, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, and the filtrate was spun dry to give the title compound 1(420 g, 1.56 mol, 121%) as a colorless oily liquid.
Step 2:
dimethyl sulfoxide (2000 mL) was added to a 5L three-necked flask, sodium hydrogen (95 g, 2.375 mol) was added at 10 ℃, and trimethyl sulfoxide iodide (500 g,2.273 mol) was added in portions to the reaction flask, and the mixture was stirred for 1 hour after the addition. Then, a solution of Compound 1(420 g, 1.56 mol) and dimethyl sulfoxide (500 mL) was slowly added dropwise to the flask at 10 ℃ and the system was naturally stirred at room temperature for 3 hours after 1 hour of addition.
The reaction was poured into ice water, extracted with ethyl acetate (500 mL x 2), the organic phase was separated, washed with saturated brine (300 mL x 2), dried over anhydrous sodium sulfate, and the filtrate was spun dry to give the title compound 2(385 g, 1.36 mol,87.1%) as a colorless oily liquid.
And step 3:
to a 5-liter three-necked flask, compound 2(385 g, 1.36 mol) and methylene chloride (0.8L) were added; TFA (1L) was slowly added dropwise in an ice-water bath, and the system was allowed to cool to room temperature and stirred for 2 h. And cooling to 0 ℃, directly spin-drying the reaction liquid to obtain a reddish brown oily substance and the target compound 3, and directly feeding into the next step.
And 4, step 4:
dissolving the crude compound 3 obtained in the step 3 with water (1L), extracting with dichloromethane twice, transferring the water phase into a 5L three-neck flask, adding sodium carbonate to adjust the pH value to 8-9, and adding Boc in batches2O (180 g, 0.825 mol) + dioxane (0.5L) solution, addThe complete system was stirred at room temperature for 2 h. And (3) treatment: the reaction system was extracted with ethyl acetate (500 mL × 2), the organic phase was discarded, the pH of the aqueous phase was adjusted to 3 with citric acid, ethyl acetate (500 mL × 2) was added for extraction, the mixture was washed with saturated brine (300 mL × 2), dried over anhydrous sodium sulfate, and the filtrate was spun to dryness to obtain a yellow liquid, which was recrystallized to obtain the objective compound 4 (128 g, 0.563 mol, 41.5%)1H NMR (400 MHz, DMSO): 12.34(s, 1H), 3.94-3.88 (m, 4H), 1.79-1.76 (m, 1H), 1.39 (s, 9H)，1.23-1.08 (m, 2H), 。LC-MS (ESI): m/z 226.1 [M-H]-(ii) a The product spectra are shown in FIG. 1, FIG. 2 and FIG. 3.
Claims (6)
1. 5-Boc-5-azaspiro [2.3]The synthesis method of hexane-1-carboxylic acid is characterized by comprising the following steps: firstly, 1-BOC-3-azetidinone reacts with diethyl phosphono acetic acid tert-butyl ester in tetrahydrofuran solution under the action of sodium hydrogen, and then 1-BOC-3-azetidinone is added for reaction to generate a compound 1; secondly, reacting the compound 1 with trimethyl sulfoxide iodide in dimethyl sulfoxide solution under the action of sodium hydrogen to generate a compound 2; thirdly, reacting the compound 2 with trifluoroacetic acid in a dichloromethane solution at room temperature to generate a compound 3; in the fourth step, compound 3 is reacted with Boc in dioxane aqueous solution under the action of sodium carbonate at room temperature2O reacts to generate a target compound 4; the synthesis route is as follows:
2. the process of claim 1, wherein the synthesis of 5-Boc-5-azaspiro [2.3] hexane-1-carboxylic acid comprises: the reaction was carried out at 0 ℃ for 4 hours.
3. The process of claim 1, wherein the synthesis of 5-Boc-5-azaspiro [2.3] hexane-1-carboxylic acid comprises: the second step reaction temperature is 10 ℃, and the reaction time is 5 hours.
4. The process of claim 1, wherein the synthesis of 5-Boc-5-azaspiro [2.3] hexane-1-carboxylic acid comprises: the third step reaction time is 2 hours.
5. The process of claim 1, wherein the synthesis of 5-Boc-5-azaspiro [2.3] hexane-1-carboxylic acid comprises: and in the fourth step, the volume ratio of dioxane to water is =1: 2.
6. The process of claim 1, wherein the synthesis of 5-Boc-5-azaspiro [2.3] hexane-1-carboxylic acid comprises: the fourth step was carried out for 2 hours.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104619709A (en) * | 2012-07-13 | 2015-05-13 | Ucb生物制药私人有限公司 | Imidazopyridine derivatives as modulators of TNF activity |
| WO2020052649A1 (en) * | 2018-09-13 | 2020-03-19 | 南京明德新药研发有限公司 | Cyclopropylamine compound as lsd1 inhibitor and use thereof |
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- 2021-12-01 CN CN202111449510.3A patent/CN114085176A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104619709A (en) * | 2012-07-13 | 2015-05-13 | Ucb生物制药私人有限公司 | Imidazopyridine derivatives as modulators of TNF activity |
| WO2020052649A1 (en) * | 2018-09-13 | 2020-03-19 | 南京明德新药研发有限公司 | Cyclopropylamine compound as lsd1 inhibitor and use thereof |
| CN112689638A (en) * | 2018-09-13 | 2021-04-20 | 南京明德新药研发有限公司 | Cyclopropylamine compound serving as LSD1 inhibitor and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| ANDRII MALASHCHUK等: "Monoprotected Diamines Derived from 1, 5-Disubstituted (Aza)spiro[2.3]hexane Scaffolds", EUR. J. ORG. CHEM., 4 February 2021 (2021-02-04), pages 6570 - 6579 * |
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