CN105367528A - Triazole intermediate (D)-1-(1-cycloalkyl secondary amino)-2-(2-tetrahydropyranyl)oxo-1-acetone compounds and synthetic method - Google Patents
Triazole intermediate (D)-1-(1-cycloalkyl secondary amino)-2-(2-tetrahydropyranyl)oxo-1-acetone compounds and synthetic method Download PDFInfo
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- CN105367528A CN105367528A CN201510758692.0A CN201510758692A CN105367528A CN 105367528 A CN105367528 A CN 105367528A CN 201510758692 A CN201510758692 A CN 201510758692A CN 105367528 A CN105367528 A CN 105367528A
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- 0 *C1OCC[N+]*1 Chemical compound *C1OCC[N+]*1 0.000 description 2
- DLWDSPDNWLUHQP-UHFFFAOYSA-N CCCCCC1OC1[I](C)OC1N(C)CCCC1 Chemical compound CCCCCC1OC1[I](C)OC1N(C)CCCC1 DLWDSPDNWLUHQP-UHFFFAOYSA-N 0.000 description 1
- ZCVFXBITHMGTCA-PZORYLMUSA-N CCCCCN(CI)C([C@@H](C)OC1OCCCC1)=O Chemical compound CCCCCN(CI)C([C@@H](C)OC1OCCCC1)=O ZCVFXBITHMGTCA-PZORYLMUSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/10—Oxygen atoms
- C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
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Abstract
The invention discloses triazole intermediate (D)-1-(1-cycloalkyl secondary amino)-2-(2-tetrahydropyranyl)oxo-1-acetone compounds, and the general formula of the compounds is shown in the specification, and in the formula, n is equal to 1-5. A preparation method of the compounds I comprises the following steps: (1) under protection of N2, reacting methyl D-lactate with cycloalkyl secondary amine at 30-60 DEG C by taking cycloalkyl secondary amine as a solvent, so as to prepare a key intermediate II; and (2) under protection of N2, dissolving the key intermediate II in an organic solvent, performing room-temperature reaction with 3,4-dihydropyran by taking an organic strong acid as a catalyst, so as to prepare a compound I shown in the specification, and n is equal to 1-5. The compounds are novel in structure, also synthesis steps are simple, yield is high, and production cost is low.
Description
Technical field
The present invention relates to medical art, specifically a kind of triazole type medicine intermediate (D)-1-(1-cycloalkanes secondary amine)-2-(2-THP trtrahydropyranyl) oxygen-1-acetone compounds and synthetic method.
Background technology
Fungi infestation sickness rate continues to rise, and has become the one of the main reasons causing global infectious diseases associated death.Triazole type medicine is a large primary categories of current antifungal drug, common triazole type medicine comprises as Chinese mugwort Saperconazole (Isavuconazole), in fluconazole (Ravuconazole), Chinese mugwort fluconazole (Efinaconazole), albaconazole (Albaconazole) etc.Existing these medicines of synthesis method has route more complicated, reaction yield is low, solvent is expensive, have toxicity, security is low, be difficult to the shortcomings such as industrialization, as international monopoly PCTInt.Appl., 2005014583, PCTInt.Appl., 9839305, all adopt morpholine to react as reaction reagent and methyl lactate, reactions steps is loaded down with trivial details, need to add reaction solvent in addition, reaction yield is lower, and reaction process need add other organic solvents.
Summary of the invention
The invention provides a kind of triazole type medicine intermediate (D)-1-(1-cycloalkanes secondary amine)-2-(2-THP trtrahydropyranyl) oxygen-1-acetone compounds and synthetic method, such compou nd synthesis method is simple, and reaction conversion ratio is high.
The technical solution used in the present invention is: a kind of triazole type medicine intermediate (D)-1-(1-cycloalkanes secondary amine)-2-(2-THP trtrahydropyranyl) oxygen-1-acetone compounds, and it is characterized in that, this compound structure general formula is as follows:
, wherein, n=1 ~ 5.
The preparation method of above-claimed cpd I, comprises the following steps: (1) N
2under protection, D-ALPHA-Hydroxypropionic acid methyl esters and cycloalkanes secondary amine under 30 ~ 60 ° of C, preferably 40 ~ 50 ° of C; using cycloalkanes secondary amine as solvent reaction, obtained key intermediate II, wherein; the mol ratio of D-ALPHA-Hydroxypropionic acid methyl esters and cycloalkanes secondary amine is 1:1 ~ 1:1.3, preferred 1:1 ~ 1:1.1, more preferably 1:1.05.
(2) N
2under protection, intermediate II is dissolved in organic solvent, with 3; 4-dihydropyrane is using organic acid as catalyzer, and room temperature reaction, obtains chemical compounds I; wherein n=1 ~ 5, the mol ratio of intermediate II and catalyzer is 1:0.05 ~ 0.1, preferred 1:0.08 ~ 0.1; more preferably 1:0.1; the mol ratio of intermediate II and 3,4-dihydropyrane is 1:1 ~ 1:1.4, preferred 1:1 ~ 1.3; more preferably 1:1.1, reaction formula is as follows:
。
Preferably, described cycloalkanes secondary amine is Pyrrolidine.
Preferably, in step (2), described organic acid is tosic acid or methylsulfonic acid, and described organic solvent is tetrahydrofuran (THF).
In step (2), during dropping catalyzer, temperature of reaction is no more than 0 ° of C, and during dropping 3,4-dihydropyrane, temperature of reaction is no more than 20 ° of C, and when the complete temperature of reaction of all reagent dropwise controls at 25 ° of C, the reaction times is 5 ~ 6h.
Advantage of the present invention: in the present invention, this compounds not only novel structure, synthesis step is simple, reaction conversion ratio is high, step (1) does not need another solubilizing agent in reaction process, reduce the cost of reaction, therefore great exploitation potential for its and good application prospect.
Embodiment
In order to deepen the understanding of the present invention, below in conjunction with embodiment, the invention will be further described, and this embodiment only for explaining the present invention, does not form limiting the scope of the present invention.
Embodiment 1:
(1) synthesis (n=2) of intermediate II: add 360Kg (3.46Kmol) D-ALPHA-Hydroxypropionic acid methyl esters in the reactor of 1000L, logical nitrogen protection, drips 246Kg Pyrrolidine (1.0eq), stirring reaction 8h under 45 ° of C.Concentrate the by-product carbinol that major part reaction produces, add 12.3Kg Pyrrolidine (0.05eq), nitrogen protection, under 40 ~ 50 ° of C, continue reaction 5h.Concentrated by reaction solution, obtain orange-yellow oily liquids (D)-1-(1-pyrrolidyl)-2-hydroxyl-1-acetone 490Kg (theoretical yield 495Kg), i.e. intermediate II, yield is 98.99%.Product is dissolved in deuterochloroform, is characterized by proton nmr spectra, and each peak ownership is as follows, 1.39 (d, 3 Η), 1.97 (q, 4H), 3.46 (q, 4H), 4.34 (q, 1H).Product structure formula is as follows:
。
(2) preparation (n=2) of chemical compounds I: 490Kg the first step product, joins in the reactor of 1000L, adds 700L tetrahydrofuran (THF), passes into nitrogen protection.Add tosic acid 59Kg (0.1eq), temperature is not more than 0 ° of C in batches.Then drip 3, the 4-dihydropyrane (1.1eq) of 318Kg, control temperature is no more than 20 ° of C, drips off rear 25 ° of C reaction.Monitoring reaction after 5h, after question response is complete, with the Na of 12%
2cO
3(400Kg) aqueous solution cancellation reaction, leave standstill 30min separatory, the tertiary fourth methyl ether back extraction of water layer 300L, merge organic layer, the salt solution 300Kg with 15% washs once, organic layer 25Kg anhydrous sodium sulfate drying 2h, filter, filtrate obtains 770Kg pale yellowish oil liquid (D)-1-(1-pyrrolidyl)-2-(2-THP trtrahydropyranyl) oxygen-1-acetone at 30 ~ 55 ° of C decompression precipitations, i.e. chemical compounds I, yield is 97.47%.Product is dissolved in deuterochloroform, is characterized by proton nmr spectra, and each peak ownership is as follows, 1.39 (d, 3H), 1.55 ~ 1.65 (m, 6H), 1.97 (q, 4H), 3.46 (q, 4H), 3.55 (t, 2H), 3.96 (q, 1H), 4.95 (t, 1H).Product structure formula is as follows:
。
Embodiment 2:
(1) synthesis (n=3) of intermediate II: add 360Kg (3.46Kmol) D-ALPHA-Hydroxypropionic acid methyl esters in the reactor of 1000L, logical nitrogen protection, drips 294.62Kg piperidines (1.0eq), stirring reaction 8h under 45 ° of C.Concentrate most of by-product carbinol in reaction solution, add 14.73Kg piperidines (0.05eq), nitrogen protection, under 45 ° of C, continue reaction 5h.Concentrated by reaction solution, obtain orange-yellow oily liquids (D)-1-(1-piperidines alkyl)-2-hydroxyl-1-acetone 535Kg (theoretical yield 543Kg), i.e. intermediate II, yield is 98.53%.Product is dissolved in deuterochloroform, is characterized by proton nmr spectra, and each peak ownership is as follows, 1.39 (d, 3H), 1.50-1.55 (m, 6H), 3.34 (t, 4H), 4.34 (q, 1H).Product structure formula is as follows:
。
(2) preparation (n=3) of chemical compounds I: 535Kg intermediate II joins in the reactor of 1000L; add 750L tetrahydrofuran (THF); pass into nitrogen protection; add tosic acid 58.7Kg (0.1eq) in batches; temperature, more than 0 ° of C, then drips 3, the 4-dihydropyrane (1.1eq) of 315.5Kg; control temperature is no more than 20 ° of C, drips off rear 25 ° of C reaction.Monitoring reaction after 5h, after question response is complete, with the Na of 12%
2cO
3(400Kg) aqueous solution cancellation reaction, leave standstill 30min separatory, the tertiary fourth methyl ether back extraction of water layer 300L, merge organic layer, the salt solution 300Kg with 15% washs once, organic layer 25Kg anhydrous sodium sulfate drying 2h, filter, filtrate obtains 785Kg pale yellowish oil (D)-1-(1-piperidines alkyl)-2-(2-THP trtrahydropyranyl) oxygen-1-acetone at 30 ~ 55 ° of C decompression precipitations, i.e. chemical compounds I, yield is 95.97%.Product is dissolved in deuterochloroform, is characterized by proton nmr spectra, and each peak ownership is as follows, 1.39 (d, 3H), 1.50-1.55 (m, 6H), 1.55 ~ 1.65 (m, 6H), 3.34 (q, 4H), 3.55 (t, 2H), 3.96 (q, 1H), 4.95 (t, 1H).Product structure formula is as follows:
。
Embodiment 3:
(1) synthesis (n=1) of intermediate II: add 360Kg (3.46Kmol) D-ALPHA-Hydroxypropionic acid methyl esters in the reactor of 1000L, logical nitrogen protection, drip 198Kg azetidine (1.0eq), stirring reaction 8h under 40 ° of C, concentrate most of by-product carbinol in reaction solution, add 9.88Kg azetidine (0.05eq), nitrogen protection, reaction 5h is continued under 40 ° of C, reaction solution is concentrated, obtain orange-yellow oily liquids (D)-1-(1-azo-cycle butane group)-2-hydroxyl-1-acetone 200Kg(theoretical yield 446Kg), yield is 44.84%, product is dissolved in deuterochloroform, characterized by proton nmr spectra, following 1.39 (the d of each peak ownership, 3H), 2.20-2.23 (m, 2H), 3.34 (t, 4H), 4.34 (q, 1H), product structure formula is as follows:
。
(2) preparation (n=1) of chemical compounds I: 200Kg the first step product (D)-1-(1-azo-cycle butane group)-2-hydroxyl-1-acetone is joined in the reactor of 500L, add 300L tetrahydrofuran (THF), pass into nitrogen protection, add tosic acid 26.66Kg (0.1eq) in batches, temperature is not more than 0 ° of C, then 3 of 143Kg are dripped, 4-dihydropyrane (1.1eq), control temperature is no more than 20 ° of C, drip off rear 25 ° of C reaction, monitoring reaction after 5h, after question response is complete, with the Na of 12%
2cO
3(200Kg) aqueous solution cancellation reaction, leave standstill 30min separatory, the tertiary fourth methyl ether back extraction of water layer 150L, merge organic layer, salt solution 100Kg with 15% washs once, organic layer 10Kg anhydrous sodium sulfate drying 2h, filter, filtrate obtains 200Kg pale yellowish oil (D)-1-(1-azetidinyl)-2-(2-THP trtrahydropyranyl) oxygen-1-acetone at 30 ~ 55 ° of C decompression precipitations, yield is 60.61%, product is dissolved in deuterochloroform, characterized by proton nmr spectra, following 1.39 (the d of each peak ownership, 3H), 1.55 ~ 1.65 (m, 6H), 2.20-2.23 (m, 2H), 3.55 (t, 2H), 3.84 (t, 4H), 3.96 (q, 1H), 4.95 (t, 1H), product structure formula is as follows:
。
Embodiment 4
(1) synthesis (n=4) of intermediate II: add 360Kg (3.46Kmol) D-ALPHA-Hydroxypropionic acid methyl esters in the reactor of 1000L, logical nitrogen protection, drip 343Kg azepan (1.0eq), stirring reaction 8h under 60 ° of C, concentrate most of by-product carbinol in reaction solution, add 17Kg azepan (0.05eq), nitrogen protection, reaction 5h is continued under 60 ° of C, reaction solution is concentrated, obtain orange-yellow oily liquids (D)-1-(1-azo-cycle heptane base)-2-hydroxyl-1-acetone 390Kg (theoretical yield 578Kg), yield is 67.47%, product is dissolved in deuterochloroform, characterized by proton nmr spectra, each peak ownership is as follows, 1.39 (d, 3H), 1.50-1.53 (m, 8H), 3.34 (t, 4H), 4.34 (q, 1H), product structure formula is as follows:
。
(2) preparation (n=4) of chemical compounds I: 300Kg the first step product (D)-1-(1-azo-cycle heptane base)-2-hydroxyl-1-acetone is joined in the reactor of 1000L, add 500L tetrahydrofuran (THF), pass into nitrogen protection, add tosic acid 30Kg (0.1eq) in batches, temperature is not more than 0 ° of C, then 3 of 162Kg are dripped, 4-dihydropyrane (1.1eq), control temperature is no more than 20 ° of C, drip off rear 25 ° of C reaction, monitoring reaction after 5h, after question response is complete, with the Na of 12%
2cO
3(300Kg) aqueous solution cancellation reaction, leave standstill 30min separatory, the tertiary fourth methyl ether back extraction of water layer 200L, merge organic layer, salt solution 200Kg with 15% washs once, organic layer 20Kg anhydrous sodium sulfate drying 2h, filter, filtrate obtains 230Kg pale yellowish oil (D)-1-(1-azepan base)-2-(2-THP trtrahydropyranyl) oxygen-1-acetone at 30 ~ 55 ° of C decompression precipitations, yield is 51.41%, product is dissolved in deuterochloroform, characterized by proton nmr spectra, following 1.39 (the d of each peak ownership, 3H), 1.50-1.53 (m, 8H), 1.55 ~ 1.65 (m, 6H), 3.34 (t, 4H), 3.55 (t, 2H), 3.96 (q, 1H), , 4.95 (t, 1H), product structure formula is as follows:
。
Embodiment 5
(1) synthesis (n=5) of intermediate II: add 360Kg (3.46Kmol) D-ALPHA-Hydroxypropionic acid methyl esters in the reactor of 1000L, logical nitrogen protection, drip 391Kg Azacyclooctane (1.0eq), stirring reaction 8h under 60 ° of C, concentrate most of by-product carbinol in reaction solution, add 19.6Kg Azacyclooctane (0.05eq), nitrogen protection, reaction 5h is continued under 60 ° of C, reaction solution is concentrated, obtain orange-yellow oily liquids (D)-1-(1-azo-cycle octyl)-2-hydroxyl-1-acetone 410Kg (theoretical yield 640Kg), yield is 64.06%, product is dissolved in deuterochloroform, characterized by proton nmr spectra, following 1.39 (the d of each peak ownership, 3H), 1.45-1.55 (m, 10H), 3.34 (t, 4H), 4.34 (q, 1H), product structure formula is as follows:
。
(2) preparation (n=5) of chemical compounds I: 400Kg the first step product (D)-1-(1-azo-cycle octyl)-2-hydroxyl-1-acetone is joined in the reactor of 1000L, add 800L tetrahydrofuran (THF), pass into nitrogen protection, add tosic acid 37.2Kg (0.1eq) in batches, temperature is not more than 0 ° of C, then 3 of 200Kg are dripped, 4-dihydropyrane (1.1eq), control temperature is no more than 20 ° of C, drip off rear 25 ° of C reaction, monitoring reaction after 5h, after question response is complete, with the Na of 12%
2cO
3(400Kg) aqueous solution cancellation reaction, leave standstill 30min separatory, the tertiary fourth methyl ether back extraction of water layer 300L, merge organic layer, salt solution 300Kg with 15% washs once, organic layer 30Kg anhydrous sodium sulfate drying 2h, filter, filtrate obtains 290Kg yellow oily (D)-1-(1-Azacyclooctane base)-2-(2-THP trtrahydropyranyl) oxygen-1-acetone at 30 ~ 55 ° of C decompression precipitations, yield is 50.05%, product is dissolved in deuterochloroform, characterized by proton nmr spectra, following 1.39 (the d of each peak ownership, 3H), 1.30-1.32 (m, 6H), 1.52-1.55 (m, 4H), 1.62-1.86 (m, 8H), 3.20 (t, 2H), 3.55 (t, 2H), 3.96 (q, 1H), 4.95 (t, 1H), .Product structure formula is as follows:
。
Claims (9)
1. triazole type medicine intermediate (D)-1-(1-cycloalkanes secondary amine)-2-(2-THP trtrahydropyranyl) oxygen-1-acetone compounds, it is characterized in that, this compound structure general formula is as follows:
Wherein, n=1 ~ 5.
2. the preparation method of a kind of triazole type medicine intermediate (D)-1-(1-cycloalkanes secondary amine)-2-(2-THP trtrahydropyranyl) oxygen-1-acetone compounds according to claim 1, it is characterized in that, comprise the following steps: (1) N
2under protection, D-ALPHA-Hydroxypropionic acid methyl esters and cycloalkanes secondary amine react using cycloalkanes secondary amine as solvent (n=1 ~ 5) under 30 ~ 60 ° of C, and obtained key intermediate II, wherein, the mol ratio of D-ALPHA-Hydroxypropionic acid methyl esters and cycloalkanes secondary amine is 1:1 ~ 1:1.3, (2) N
2under protection; intermediate II is dissolved in organic solvent; with 3,4-dihydropyrane using organic acid as catalyzer, room temperature reaction; obtained chemical compounds I; wherein n=1 ~ 5, the mol ratio of intermediate II and catalyzer is 1:0.05 ~ 0.1, intermediate II and 3; the mol ratio of 4-dihydropyrane is 1:1 ~ 1:1.4, and reaction formula is as follows:
。
3. the preparation method of a kind of triazole type medicine intermediate (D)-1-(1-cycloalkanes secondary amine)-2-(2-THP trtrahydropyranyl) oxygen-1-acetone compounds according to claim 2, it is characterized in that, described cycloalkanes secondary amine is Pyrrolidine.
4. the preparation method of a kind of triazole type medicine intermediate (D)-1-(1-cycloalkanes secondary amine)-2-(2-THP trtrahydropyranyl) oxygen-1-acetone compounds according to Claims 2 or 3, it is characterized in that, the temperature of reaction of step (1) is 40 ~ 50 ° of C.
5. the preparation method of a kind of triazole type medicine intermediate (D)-1-(1-cycloalkanes secondary amine)-2-(2-THP trtrahydropyranyl) oxygen-1-acetone compounds according to Claims 2 or 3, it is characterized in that, in step (1), the mol ratio of D-ALPHA-Hydroxypropionic acid methyl esters and cycloalkanes secondary amine is 1:1.05.
6. the preparation method of a kind of triazole type medicine intermediate (D)-1-(1-cycloalkanes secondary amine)-2-(2-THP trtrahydropyranyl) oxygen-1-acetone compounds according to Claims 2 or 3, it is characterized in that, in step (2), described organic acid is tosic acid or methylsulfonic acid, and described organic solvent is tetrahydrofuran (THF).
7. the preparation method of a kind of triazole type medicine intermediate (D)-1-(1-cycloalkanes secondary amine)-2-(2-THP trtrahydropyranyl) oxygen-1-acetone compounds according to Claims 2 or 3, it is characterized in that, in step (2), the mol ratio of intermediate II and catalyzer is 1:0.1.
8. the preparation method of a kind of triazole type medicine intermediate (D)-1-(1-cycloalkanes secondary amine)-2-(2-THP trtrahydropyranyl) oxygen-1-acetone compounds according to Claims 2 or 3, it is characterized in that, in step (2), the mol ratio of intermediate II and 3,4-dihydropyrane is 1:1.1.
9. the preparation method of a kind of triazole type medicine intermediate (D)-1-(1-cycloalkanes secondary amine)-2-(2-THP trtrahydropyranyl) oxygen-1-acetone compounds according to Claims 2 or 3, it is characterized in that, in step (2), during dropping catalyzer, temperature of reaction is no more than 0 ° of C, during dropping 3,4-dihydropyrane, temperature of reaction is no more than 20 ° of C.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0421210A2 (en) * | 1989-09-26 | 1991-04-10 | Takeda Chemical Industries, Ltd. | Triazole compounds, their production and use |
| US6133485A (en) * | 1998-04-15 | 2000-10-17 | Synphar Laboratories, Inc. | Asymmetric synthesis of 2-(2,4-difluorophenyl)-1-heterocycl-1-yl butan-2,3-diols |
| US6300353B1 (en) * | 1998-03-06 | 2001-10-09 | Basilea Pharmaceutica Ag, A Swiss Company | Azoles for treatment of fungal infections |
| CN101321522A (en) * | 2005-12-01 | 2008-12-10 | 巴斯利尔药物股份公司 | Process for the manufacture of epoxy triazole derivatives |
-
2015
- 2015-11-10 CN CN201510758692.0A patent/CN105367528A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0421210A2 (en) * | 1989-09-26 | 1991-04-10 | Takeda Chemical Industries, Ltd. | Triazole compounds, their production and use |
| US6300353B1 (en) * | 1998-03-06 | 2001-10-09 | Basilea Pharmaceutica Ag, A Swiss Company | Azoles for treatment of fungal infections |
| US6133485A (en) * | 1998-04-15 | 2000-10-17 | Synphar Laboratories, Inc. | Asymmetric synthesis of 2-(2,4-difluorophenyl)-1-heterocycl-1-yl butan-2,3-diols |
| CN101321522A (en) * | 2005-12-01 | 2008-12-10 | 巴斯利尔药物股份公司 | Process for the manufacture of epoxy triazole derivatives |
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