CN109503582A - The synthetic method of cis- spiral shell [piperidines simultaneously -4,1 '-pyrrolo- [3,4-C] pyrroles] -1- t-butyl formate - Google Patents
The synthetic method of cis- spiral shell [piperidines simultaneously -4,1 '-pyrrolo- [3,4-C] pyrroles] -1- t-butyl formate Download PDFInfo
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- CN109503582A CN109503582A CN201811539863.0A CN201811539863A CN109503582A CN 109503582 A CN109503582 A CN 109503582A CN 201811539863 A CN201811539863 A CN 201811539863A CN 109503582 A CN109503582 A CN 109503582A
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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Abstract
The present invention relates to the synthetic methods of cis- 5'- benzyl -3'- oxygen subunit hexahydro -2'H- spiral shell [piperidines simultaneously -4,1'- pyrrolo- [3,4-C] pyrroles] -1- t-butyl formate, the technical issues of mainly solution currently without suitable Industrialized synthesis method.The present invention divides four steps, and ethyl propiolate is dissolved in ethyl acetate by the first step, toward the ethanol system dissolved with 4- nitro piperidines -1- carboxylate and tetrabutyl ammonium fluoride in temperature control be added dropwise, reaction obtain compound 2；Second step obtains compound 3 toward dissolved with trifluoroacetic acid reaction is added dropwise in compound 2 and nitrogen-benzyl -1- methoxyl group-nitrogen-((trimethyl silyl) methyl) methylamine toluene system；Step 3: Raney's nickel is added into the ethyl alcohol dissolved with compound 3, then hydrogenation obtains compound 4；Step 4: compound 4 is dissolved into tetrahydrofuran, the reaction of two (trimethyl silicane) lithium amides is added, it is post-treated to obtain compound 5.
Description
Technical field
The present invention relates to the synthesis sides of cis- spiral shell [piperidines simultaneously -4,1'- pyrrolo- [3,4-C] pyrroles] -1- t-butyl formate
The cis- 5'- benzyl -3'- oxygen subunit hexahydro -2'H- spiral shell of method, i.e. compound [piperidines simultaneously -4,1'- pyrrolo- [3,4-C] pyrroles] -
The synthetic method of 1- t-butyl formate.
Background technique
The cis- 5'- benzyl -3'- oxygen subunit hexahydro -2'H- spiral shell of compound [piperidines simultaneously -4,1'- pyrrolo- [3,4-C] pyrrole
Cough up] -1- t-butyl formate (MFCD27997312) and relevant derivative have in pharmaceutical chemistry and organic synthesis and answer extensively
With.Cis- 5'- benzyl -3'- oxygen subunit hexahydro -2'H- spiral shell [piperidines simultaneously -4,1'- pyrrolo- [3,4-C] pyrroles] -1- first at present
The synthetic method of tert-butyl acrylate there is no literature reported on.Easy to operate therefore, it is necessary to develop a raw material to be easy to get, reaction is easy to control
System, overall yield are suitble to, and are suitble to the synthetic method of industrialized production.
Summary of the invention
It is easy to operate the purpose of the present invention is developing one kind to be easy to get with raw material, react easily controllable, yield is higher
Cis- 5'- benzyl -3'- oxygen subunit hexahydro -2'H- spiral shell [piperidines simultaneously -4,1'- pyrrolo- [3,4-C] pyrroles] tertiary fourth of -1- formic acid
The synthetic method of ester.The technical issues of mainly solving currently without document report synthetic method.
A kind of technical solution of the present invention: cis- 5'- benzyl -3'- oxygen subunit hexahydro -2'H- spiral shell [piperidines simultaneously -4,1'-
Pyrrolo- [3,4-C] pyrroles] -1- t-butyl formate synthetic method.The present invention divides four steps, and the first step is molten by ethyl propiolate
In ethyl acetate, toward the ethanol system dissolved with 4- nitro piperidines -1- carboxylate and tetrabutyl ammonium fluoride in temperature control drip
Add, reaction obtains compound 2.Second step, toward dissolved with compound 2 and nitrogen-benzyl -1- methoxyl group-nitrogen-((trimethyl first silicon
Alkyl) methyl) methylamine toluene system in be added dropwise trifluoroacetic acid reaction, obtain compound 3.Step 3: toward dissolved with compound 3
Raney's nickel is added in ethyl alcohol, then hydrogenation obtains compound 4.Step 4: compound 4 is dissolved into tetrahydrofuran, add
Enter the reaction of two (trimethyl silicane) lithium amides, system is quenched with saturated ammonium chloride, and by organic layer liquid separation, water is extracted with ethyl acetate
Phase, combined organic phase are washed with saturated common salt, are dried, filtered with anhydrous sodium sulfate, are spin-dried for obtaining crude product, crude product second
Acetoacetic ester is recrystallized to give compound as white solid 5, and reaction equation is as follows:
。
10 DEG C -15 DEG C of first step charge temperature, 20 DEG C the reaction time 20 hours；Second step adds in the case where 70 DEG C of stirrings
Enter reactant, 90-100 DEG C is stirred to react 2 hours；50 DEG C of third step, 20 psi are stirred to react 4 hours；The stirring of 4th 15 DEG C of step
Reaction 1 hour.
The Chinese paraphrase that the present invention abridges: TLC: thin-layered chromatography；LiHMDS: two (trimethyl silicane) lithium amides.
Beneficial effects of the present invention: rationally, which employs four steps to synthesize cis- 5'- benzene first for reaction process design of the present invention
Base -3'- oxygen subunit hexahydro -2'H- spiral shell [piperidines simultaneously -4,1'- pyrrolo- [3,4-C] pyrroles] -1- t-butyl formate, has original creation
Property, this method route is short, and total recovery is high, and reaction is easy to amplify, easy to operate.Cis- 5'- benzyl -3'- oxygen subunit is filled up
The blank of hexahydro -2'H- spiral shell [piperidines simultaneously -4,1'- pyrrolo- [3,4-C] pyrroles] -1- t-butyl formate Industrialized synthesis method.
Specific embodiment
Reaction equation of the present invention is as follows:
Step 1: by 4- nitro piperidines -1- carboxylate (265 g, 1.15 mol) and tetrabutyl ammonium fluoride, (1 rubs
You, 2.30 L) it is dissolved in two liters of ethyl acetate, it is added dropwise inside at 10-15 DEG C.The system is small in 20 DEG C of stirrings 20
When.TLC (petrol ether/ethyl acetate volume ratio=2/1) shows end of reaction.Reaction solution is washed with water three times, and one liter every time,
It is primary with one liter of saturated common salt washing again, it is dry with anhydrous magnesium sulfate, it is spin-dried for.Gained crude product silica gel chromatography (petroleum
Ether: ethyl acetate volume ratio=20:1 ~ 0:1) obtain compound 2 (577 g, 1.76 mol, 76.34% receipts of yellow oily
Rate).
1H NMR (400MHz, CDCl3-d6) δ = 6.93-6.89 (d, 1H), 6.03 - 6.07 (d, 1H),
4.26 - 4.20 (m, 2H), 3.90 - 3.75 (d, 2H), 3.20 - 3.15 (t, 3H), 2.62 - 2.55
(d, 2H), 1.92 - 2.15 (m, 2H), 1.50-1.47 (s, 9H), 1.25 - 1.45 (m, 3H)。
Step 2: in the case where 70 DEG C of stirrings, toward dissolved with compound 2 (116.00 g, 353.27 mmol) nitrogen-benzene
The toluene of methyl-1-methoxyl group-nitrogen-((trimethyl silyl) methyl) methylamine (167.74 g, 706.54 mmol)
In (1.5 L) system be added dropwise trifluoroacetic acid (4.03 g, 35.33 mmol), then again 90-100 DEG C be stirred to react 2 hours.
TLC (petrol ether/ethyl acetate volume ratio=3/1) shows end of reaction, is cooled to room temperature, then vacuum rotary steam.Gained is thick
Product obtain chemical combination with silica gel chromatography (petroleum ether: ethyl acetate volume ratio=100:1,50:1,20:1,10:1,0:10)
Object 3 (150.00 g, 324.99 mmol, 92.00% yield).
1H NMR (400MHz, CDCl3-d6) δ = 7.26-7.18 (m, 5H), 4.12 - 4.07 (m, 2H),
4.01 - 3.82 (m, 2H), 3.47 - 3.46 (d, 2H), 3.04 - 2.96 (m, 3H), 2.74 - 2.69
(m, 3H), 2.62 - 2.58 (m, 2H), 2.49-2.48 (m, 1H), 2.40 -2.37 (d, 2H)。
Step 3: under nitrogen protection, toward the ethyl alcohol dissolved with compound 3 (120.00 g, 259.99 mmol, 1.00)
Raney's nickel (111.37 g, 1.30 mol) are added in (1.2 L).Then again 50 DEG C, H2It is stirred four hours under (20 psi).
TLC (petrol ether/ethyl acetate volume ratio=3/1) shows end of reaction, and filtering, then decompression is spin-dried for obtaining compound 4
(99.00 g, 229.40 mmol, 88.23% yield).
1H NMR (400MHz, CDCl3-d6) δ = 7.29-7.19 (m, 5H), 4.13 - 4.10 (q, 2 H),
3.73 - 3.60 (m, 2H), 3.60 - 3.48 (d, 2H), 3.11 - 3.09 (m, 2H), 2.93 - 2.92
(m, 1H), 2.84 - 2.80 (t, 1H), 2.65-2.63 (m, 1H), 2.65 -2.51 (m, 3H), 1.46-
1.43 (m, 13H), 1.30-1.24 (m, 2H),1.21-1.19 (m, 3H)。
Step 4: it is inner that compound 4 (99.00 g, 229.39 mmol) is dissolved into tetrahydrofuran (1 L).It is stirred at 0 DEG C
LiHMDS (1.0 M, 458.79 mL) are added dropwise in the case where mixing inside, then again 15 DEG C stir 1 hour.TLC (petroleum
Ether/ethyl acetate volume ratio=3/1) display end of reaction.System is quenched with saturated ammonium chloride, by organic layer liquid separation, uses second
Acetoacetic ester (10 mL*2) aqueous phase extracted.Combined organic phase is washed with saturated common salt, dry with anhydrous sodium sulfate, mistake
Filter, is spin-dried for obtaining crude product.Crude product with re-crystallizing in ethyl acetate obtain compound as white solid 5 (48.00 g, 124.51 mmol,
54.28% yield).
1H NMR (400MHz, CDCl3-d6) δ =7.17-7.09 (m, 5H), 6.15 - 5.91 (s, 1 H),
3.74 - 3.64 (q, 2H), 3.60 - 3.48 (s, 2H), 3.16 - 3.13 (m, 2H), 2.63 - 2.61
(m, 2 H), 2.57 - 2.52 (m, 1H), 1.57-1.40 (m, 3H), 1.28 (s, 9H)。
Claims (5)
1. a kind of cis- 5'- benzyl -3'- oxygen subunit hexahydro -2'H- spiral shell [piperidines simultaneously -4,1'- pyrrolo- [3,4-C] pyrroles] -
The synthetic method of 1- t-butyl formate, it is characterized in that: the following steps are included: the first step, is dissolved in ethyl acetate for ethyl propiolate
In, toward the ethanol system dissolved with 4- nitro piperidines -1- carboxylate and tetrabutyl ammonium fluoride in temperature control be added dropwise, reaction obtains
Compound 2；Second step, toward dissolved with compound 2 and nitrogen-benzyl -1- methoxyl group-nitrogen-((trimethyl silyl) methyl) first
Trifluoroacetic acid reaction is added dropwise in the toluene system of amine, obtains compound 3；Step 3: thunder is added into the ethyl alcohol dissolved with compound 3
Buddhist nun's nickel, then hydrogenation obtains compound 4；Step 4: compound 4 is dissolved into tetrahydrofuran, two (trimethyls are added
Silicon) lithium amide reaction, system is quenched with saturated ammonium chloride, by organic layer liquid separation, be extracted with ethyl acetate water phase, merging it is organic
It is mutually washed with saturated common salt, is dried, filtered with anhydrous sodium sulfate, be spin-dried for obtaining crude product, crude product re-crystallizing in ethyl acetate
Obtain compound as white solid 5；Reaction equation is as follows:
。
[piperidines simultaneously-the 4,1'- 2. a kind of cis- 5'- benzyl -3'- oxygen subunit hexahydro -2'H- spiral shell according to claim 1
Pyrrolo- [3,4-C] pyrroles] -1- t-butyl formate synthetic method, it is characterized in that: 10 DEG C -15 DEG C of first step charge temperature, 20
DEG C the reaction time 20 hours.
[piperidines simultaneously-the 4,1'- 3. a kind of cis- 5'- benzyl -3'- oxygen subunit hexahydro -2'H- spiral shell according to claim 1
Pyrrolo- [3,4-C] pyrroles] -1- t-butyl formate synthetic method, it is characterized in that: second step in the case where 70 DEG C of stirrings plus
Enter reactant, 90-100 DEG C is stirred to react 2 hours.
[piperidines simultaneously-the 4,1'- 4. a kind of cis- 5'- benzyl -3'- oxygen subunit hexahydro -2'H- spiral shell according to claim 1
Pyrrolo- [3,4-C] pyrroles] -1- t-butyl formate synthetic method, it is characterized in that: 50 DEG C of third step, 20 psi are stirred to react
4 hours.
[piperidines simultaneously-the 4,1'- 5. a kind of cis- 5'- benzyl -3'- oxygen subunit hexahydro -2'H- spiral shell according to claim 1
Pyrrolo- [3,4-C] pyrroles] -1- t-butyl formate synthetic method, it is characterized in that: 15 DEG C of the 4th step is stirred to react 1 hour.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1242367A (en) * | 1998-06-12 | 2000-01-26 | 弗·哈夫曼-拉罗切有限公司 | Spiro [Piperidine-4,1'-pyrrolo[3,4-c] pyrrole] |
| CN1640876A (en) * | 2004-01-02 | 2005-07-20 | 上海药明康德新药开发有限公司 | Spiro dihydroindole template compound and its preparing method |
| CN102066380A (en) * | 2008-04-22 | 2011-05-18 | 先灵公司 | Phenyl-substituted 2-imino-3-methyl pyrrolo pyrimidinone compounds as BACE-1 inhibitors, compositions, and their use |
| WO2012101487A1 (en) * | 2010-12-22 | 2012-08-02 | Novartis Ag | Di/tri-aza-spiro-c9-c11alkanes |
-
2018
- 2018-12-17 CN CN201811539863.0A patent/CN109503582A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1242367A (en) * | 1998-06-12 | 2000-01-26 | 弗·哈夫曼-拉罗切有限公司 | Spiro [Piperidine-4,1'-pyrrolo[3,4-c] pyrrole] |
| CN1640876A (en) * | 2004-01-02 | 2005-07-20 | 上海药明康德新药开发有限公司 | Spiro dihydroindole template compound and its preparing method |
| CN102066380A (en) * | 2008-04-22 | 2011-05-18 | 先灵公司 | Phenyl-substituted 2-imino-3-methyl pyrrolo pyrimidinone compounds as BACE-1 inhibitors, compositions, and their use |
| WO2012101487A1 (en) * | 2010-12-22 | 2012-08-02 | Novartis Ag | Di/tri-aza-spiro-c9-c11alkanes |
Non-Patent Citations (1)
| Title |
|---|
| RENATA KUCIAK AND WOJCIECH SAS: "Synthesis of branched-chain azafuranose derivatives from secondary nitroalkanes. Facile synthesis of (±) 4-amino-4,4-bis(hydroxymethyl)-4-deoxythreonic-1,4-lactam", 《TETRAHEDRON LETTERS》 * |
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