CN102267995A - Method for preparing diazaspiro compound - Google Patents
Method for preparing diazaspiro compound Download PDFInfo
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- CN102267995A CN102267995A CN2010101975462A CN201010197546A CN102267995A CN 102267995 A CN102267995 A CN 102267995A CN 2010101975462 A CN2010101975462 A CN 2010101975462A CN 201010197546 A CN201010197546 A CN 201010197546A CN 102267995 A CN102267995 A CN 102267995A
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- 0 *N(CCC1)C1C(O)=O Chemical compound *N(CCC1)C1C(O)=O 0.000 description 8
- NFCRQDOCGHYPRW-UHFFFAOYSA-N CC(C)(C)OC(N(CCCC1)C1(CCCN1)C1=O)=O Chemical compound CC(C)(C)OC(N(CCCC1)C1(CCCN1)C1=O)=O NFCRQDOCGHYPRW-UHFFFAOYSA-N 0.000 description 1
- PVMJFJDVCVNWQN-UHFFFAOYSA-N CC(C)(C)OC(N(CCCC1)C1C(OC)=O)=O Chemical compound CC(C)(C)OC(N(CCCC1)C1C(OC)=O)=O PVMJFJDVCVNWQN-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention belongs to the technical field of drug synthesis. In the prior art, the reactions for preparing diazaspiro compounds have disadvantages of requirement of a plurality of expensive regents, requirement of low temperature operation, and the like. The purpose of the invention is to solve the disadvantages in the prior art. The invention provides a method for preparing the diazaspiro compound. The prepared diazaspiro compound has a structure represented by a formula I or a formula VI. The method is characterized in that: a compound represented by a formula V is adopted as an initial raw material; the method comprises the following steps: a, removing hydrogen positioned on the site 1 of the compound represented by the formula V through a deprotonation regent, followed by carrying out an alkylation reaction with a two terminal-halogenated saturated chain alkane represented by the formula III to form a first intermediate product represented by the formula II; b, substituting a halogen X2 on the carbon positioned on the site 2 of the first intermediate product represented by the formula II through an azide regent to form a second intermediate product represented by the formula IV; c, carrying out a reduction cyclization reaction for the second intermediate product represented by the formula IV to form the diazaspiro compound represented by the formula I; d, carrying out a reduction reaction for the diazaspiro compound represented by the formula I to obtain the diazaspiro compound represented by the formula VI.
Description
Technical field
The invention belongs to technical field of medicine synthesis, relate to a kind of method for preparing the intermediate of important medicine and new drug development, described intermediate is diazaspiracyclic compounds in the present invention, and the structure that all has formula I or formula VI, the relevant limited explanation that this specification sheets is all deferred in the various qualifications (for example X, m, n or the like) of this structure, preparation method provided by the invention has optimized the synthetic route of preparation formula I or VI, has increased the yield of diazaspiracyclic compounds formula I when simplifying reactions steps.
Background technology
The diazaspiracyclic compounds is important medicine of a class and new drug development intermediate, and its importance in medical research is existing the description in prior art document (seeing patent CN101081851 or Syn.Comm., 2007,3793).
Have now found that, class branch diazaspiracyclic diamine compound to the diazaspiracyclic compounds, carry out structural transformation, can the physiologically active of husky star antibiotic medicine be improved a lot, existing document (J.Med.Chem., 1990,33,2270) just reported a kind of diazaspiracyclic diamine compound formula behind structure of modification 1..
The another kind of diaza spiro cyclic amide compounds that branches into of diazaspiracyclic compounds, because it is this compounds molecule has rigid backbone, therefore significant in the research and development of peptide kind new medicine.Existing document such as J.Org.chem.1993,58,860; J.Med.Chem.2004,47,5587; J.Org.Chem.2002,67,7587; Bioorg.Med.Chem.Lett., 2001,2449 and J.Med.Chem.2008,51,1189, reported respectively the compound formula 2., formula 3., formula 4., formula 5. with formula 6..
The compound structure that TAKEDA Pharmaceutical and Ono Pharmaceutical study 5. and 6. can be used for prevention or treatment is fat, diabetes, hypertension, hyperlipidemia, cardiac failure, diabetic complication, metabolic syndrome or various diseases of causing because of pressure etc.
In addition, the diazaspiracyclic compounds is the important intermediate of technology platform new drug development with " combinatorial chemistry " still.
The synthetic method of existing preparation diazaspiracyclic compounds has following six kinds:
Method 1 (J.Med.Chem., 1990,2270) report, overall yield 2.6%, shown in Scheme 1:
Scheme?1
(a)ClCH
2CN,LDA,40%;(b)H
2,Raney?Ni;(c)heat,36%?two?steps;(d)LAH,18%.
Method 2 (J.Med.Chem., 2004,5587; US 5,166, and 136) report, wherein PG
1=Boc, R
2Be dichlorophenyl L-Tyrosine methyl ester base, overall yield 12%, shown in Scheme 2:
Scheme?2
Reagent and productive rate: (a) LDA, propenyl bromine, 40%; (b) ozone-dimethyl sulfide, 75%; (c) NaOH, 85%; (d) dichlorophenyl L-Tyrosine methyl ester, the acetic acid sodium borohydride; (e) RT, 42%
Method 3 (J.Org.Chem.1993,860; J.Am.Chem.Soc., 1992,8778) report, wherein PG
1Be Cbz, R
1Be t-Bu, R2 is the glycine methyl ester base, overall yield 4%, shown in Scheme 3:
Scheme?3
Reagent and productive rate: (a) iso-butylene, 58%; (b) LDA, allyl bromide 98,74%; (c) trifluoracetic acid, 87%; (d) glycine methyl ester, dicyclohexylcarbodiimide, I-hydroxybenzotriazole, 83%; (e) perosmic anhydride-Periodic acid, sodium borohydride, 24%; (f) triphenyl phosphorus, diethyl azodiformate, 60%.
Method 4 (Bio.Med.Chem.Lett., 1998,8,3137) report, wherein PG
1Be Boc, R
1Be Bn, R
2Be the glycine methyl ester base, overall yield 21%.Shown in Scheme 4:
Scheme?4
Reagent and productive rate: (a) LDA, allyl bromide 98,65%; (b) borine-hydrogen peroxide, 70% (R
1Be Bn) or assorted dicyclo [3.3.1] nonane of 9-boron, hydrogen peroxide, 98% (R
1For
tBu); (c) Swern oxidation, 90%; (d) glycine methyl ester, sodium borohydride, 70%; (e) H
2/ Pd (OH) 2,90%; (f) 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide, N-methylmorpholine, 82%.
Method 5 (J.Org.Chem.2002,67,7587) report, wherein PG
1Be Boc, R
1Be t-Bu, R
2Be leucine tert-butyl ester base, overall yield 5%, shown in Scheme 5:
Reagent and productive rate: (a) LDA, allyl bromide 98,65%; (b) assorted dicyclo [3.3.1] nonane of 9-boron, hydrogen peroxide, 98%; (c) triphenyl phosphorus, iodine, 68%; (d) the leucine tert-butyl ester, 61%; (e) tetrabutyl hydrogenation amine, 80%; (f) DCC, 25%.
Method 6 (CN 101081851A and Syn.Comm., 2007,3793) report, wherein PG
1=Boc, overall yield is 25% (n=1), 36% (n=2).Shown in Scheme 6:
Reagent and productive rate: (a)
i-PrOC (O) Cl, NH
3-H
2O, 60%; (B) TFAA, Et
3N, 85%; (C) LDA, BrCH
2CH
2Cl, 55%; ClCH
2CH
2CH
2Cl, 75%; (D) Raney Ni, NH
3-H
2O, 90% (n=2); 95% (n=3).
Wherein, m=1 or m=2, n=1,2 or 3, m and n can be the same or different; X
1And X
2Be halogen, be chlorine, a kind of in the bromine or iodine, X
1With X
2Can be the same or different; PG
1And PG
2Be the substituting group on the nitrogen-atoms.
But related reaction in the above-mentioned prior art, existing needs some relatively more expensive reagent, and shortcomings such as manipulation require low temperature have more intermediate steps to need column chromatographic isolation and purification simultaneously, and overall yield is low.
Summary of the invention
Technical problem to be solved by this invention is the shortcoming that the existing method for preparing diazaspiracyclic compounds exists reaction reagent costliness, manipulation require low temperature etc. to cause reaction cost to increase, there is more intermediate steps to need column chromatographic isolation and purification simultaneously, the problem that overall yield is low, and provide a kind of method for preparing diazaspiracyclic compounds at this problem.
A kind of method for preparing diazaspiracyclic compounds of the present invention has adopted following synthetic thinking:
A kind of method for preparing diazaspiracyclic compounds, described diazaspiracyclic compounds has the structure of formula I or formula VI, and this method is an initial feed with compound formula V, comprising:
A, spend proton reagent and slough in the compound formula V hydrogen on the position No. 1, then carry out alkylated reaction, form the first intermediate product formula II with the halogenated saturated chain alkane formula III in two ends;
B, replace in the first intermediate product formula II halogen X on the carbon of position No. 2 with azide reagent
2, form the second intermediate product formula IV;
C, the second intermediate product formula IV is reduced ring closure reaction, form diazaspiracyclic compounds formula I;
D, diazaspiracyclic compounds formula I reduced obtain diazaspiracyclic compounds formula VI;
R wherein
1Be hydrogen, the alkyl that contains 1-6 carbon, tertbutyloxycarbonyl, carbobenzoxy-(Cbz) or benzyl;
R
2For containing the alkyl of 1-6 carbon;
X is an oxygen; X
1Be chlorine, bromine or iodine; X
2Be chlorine, bromine or iodine; Described X
1Reactive behavior more than or equal to X
2Reactive behavior;
M is 1,2 or 3, and n is 0,1,2 or 3, and during m=1, n ≠ 0; Y is 1,2 or 3; P is 1,2 or 3.
After adopting above-mentioned synthetic thinking, in order to make diazaspiracyclic compounds formula I of the present invention, only need the reaction of 3 steps to finish, and it is simple to operate, the yield of diazaspiracyclic compounds formula I is also higher, and the present invention has simultaneously also obtained important diazaspiracyclic compounds formula VI by diazaspiracyclic compounds formula I.
Description of drawings
The synthetic route of the method for preparing diazaspiracyclic compounds formula I and VI that Fig. 1 designs for the present invention.
Embodiment
The present invention partly provides a kind of synthetic thinking for preparing diazaspiracyclic compounds formula I or VI at summary of the invention, adopt such thinking generally can obtain higher diazaspiracyclic compounds formula I total recovery, certainly, when those skilled in the art should synthesize thinking in practical application, can adopt different reaction reagent and reaction conditionss to react, these all can produce certain influence to the total recovery of diazaspiracyclic compounds formula I, simultaneously, if selecting improperly, reaction conditions and reaction reagent also may increase reaction or the isolating difficulty of intermediate product, Given this, the technician can implement synthetic thinking of the present invention smoothly for convenience, and reach the technique effect that the present invention is scheduled to, below this embodiment from the aspect of actually operating a kind of method for preparing diazaspiracyclic compounds of the present invention is described in detail:
A kind of method for preparing diazaspiracyclic compounds, related reaction raw materials, intermediate product (first intermediate product and second intermediate product), diazaspiracyclic compounds is all consistent with the corresponding molecular structural formula that this specification sheets summary of the invention is partly introduced, summary of the invention corresponding qualification is partly also followed in the qualification of these structural formulas, and concrete reactions steps comprises:
1, alkylated reaction
Spend proton reagent and slough in the compound formula V hydrogen on the position No. 1, then carry out alkylated reaction with the halogenated saturated chain alkane formula III in two ends, formation contains the crude product of the first intermediate product formula II, halogenated saturated chain alkane formula III two ends, two ends halogen atom had better not be identical, so that cause formula III two ends and formula V reactive activity difference, form a more end substitution product (formula II).
Deprotonation reagent generally uses lithium diisopropylamine (LDA), its consumption generally should enough produce the compound formula V of sloughing No. 1 hydrogen on the position of capacity, for this embodiment, input amount (the molar weight of lithium diisopropylamine, down with) be 1.2-3 times of formula V, the reaction input amount of the halogenated saturated chain alkane formula III in two ends is 1.2-3 a times of compound formula V input amount, replaces the generation of phenomenon to prevent all combined thing formula of formula III two ends halogen V.
The general selection of the reaction solvent of alkylated reaction can help the reaction solvent that lithium diisopropylamine participates in reaction, for example THF.This embodiment finds that the temperature of reaction of above-mentioned reaction generally can finish between-30~-5 ℃, this just greatly reduces the requirement of (needing low temperature) of reaction pair equipment, and alkali has lacked the cost of reaction greatly.
2, azido reaction
Replace in the first intermediate product formula II halogen X on the carbon of position No. 2 with azide reagent
2, form the second intermediate product formula IV.When carrying out this step reaction, do not need the product formula II after the alkylation is separated purification, in fact, the technician can directly directly enter this step reaction with the crude product that contains the first intermediate product formula II that forms behind the alkylated reaction.
Described azide reagent is generally sodiumazide, its input amount be generally the formula II input amount (can proximate with alkylation reaction product as the formula II) 1.5-3 doubly, temperature of reaction is 25-85 ℃, the general selection of the reaction solvent of azido reaction can help the reaction solvent that sodiumazide participates in reaction, for example DMF, acetone, methyl alcohol or ethanol or the like, the reaction product that obtains can be directly used in next step reaction without separation.
3, reduction ring closure reaction
The second intermediate product formula IV is reduced ring closure reaction, generate diazaspiracyclic compounds formula I.Reductive agent is generally triphenyl phosphorus, and the mol ratio of triphenyl phosphorus and the reaction of the second intermediate product formula IV input is 1.0~2.0: 1.0, and organic solvent is selected acetate for use, ethyl acetate, THF, methyl alcohol, the mixture of a kind of or these solvents in the ethanol etc., temperature of reaction are generally 15 ℃~50 ℃.
4, reduction reaction
In the dry THF solution of diazaspiracyclic compounds formula I, slowly adding the reductive agent of reducing amide such as the THF solution or the lithium aluminium hydride of borine under-10 ℃~0 ℃, the mole input amount of borine or lithium aluminium hydride is generally 2-3 times of diazaspiracyclic compounds formula I mole input amount, rise to ambient temperature overnight, promptly can high yield (being generally 70%~90%) obtain diazaspiracyclic compounds formula VI behind the aftertreatment purifying.
Adopt this embodiment to prepare diazaspiracyclic compounds formula I or diazaspiracyclic compounds formula VI has 4 tangible advantages:
First, reactions steps is few, for example prepare diazaspiracyclic compounds formula I and only need the reaction of 3 steps, and per step reaction all is common reaction type, those skilled in the art can be according to the instruction of this embodiment, in conjunction with existing knowledge, draw more excellent reaction conditions easily, also promptly realize the various technique effects that the present invention mentioned easily;
Second, reaction conditions is relatively gentleer, in the related reaction of this embodiment, temperature of reaction is generally between-30 ℃~85 ℃, even if also be like this in alkylated reaction, this just greatly reduces the requirement of reaction pair equipment, and the used chemical reagent of each step reaction is easy to get and is cheap simultaneously, and these all help industrialization of the present invention;
The 3rd, reaction intermediate does not generally need purifying, directly entering next step gets final product, this embodiment finds that related respectively to go on foot byproduct of reaction generally fewer, even and if the process that these by products enter the reaction of next step reaction pair does not have any influence yet, therefore, those skilled in the art can finish the listed four-step reaction of this embodiment very easily.
The 4th, the overall yield of reaction is higher, is example with the total recovery of diazaspiracyclic compounds formula I (overall yield of promptly preceding 3 steps reaction), reacts according to this embodiment, can reach between 40%~55% usually.
Below in conjunction with specific embodiment, further illustrate the present invention.The experimental technique of unreceipted actual conditions in the following example, usually according to normal condition, or the condition of advising according to manufacturer.Ratio is based on molar weight, and per-cent is based on weight, unless stated otherwise.
Embodiment 1 (preparation of formula 14 and formula 16)
1) .N
2Protection, drip LDA 300ml (0.6mol under-15 ℃ of conditions, 2.0eq) to 200ml 4-Boc piperidine ethyl formate (formula 11) (77g, 0.3mol) dry THF (200mL) solution solvent in, finish and continue the low temperature stirring after 1 hour, with reaction solution-15 ℃ be added drop-wise to 100ml 1-bromo-3-chloropropane (formula 15) (95.0g, in dry THF solution 2.0eq), finishing slowly is warming up to RT and stirs and to spend the night; Add aqueous ammonium chloride solution next day and handle, revolve THF after, water is with ethyl acetate extraction 3 times, dry concentrating, enriched material;
2) .1) go on foot enriched material and be dissolved in 250ml DMF, add NaN in batches
3(40.0g, 2.0eq), N
2Protection and 50 ℃~60 ℃ stir down and spend the night, and inferior daily pure petroleum ether extraction 3 times merges the organic phase washing, dry concentrate enriched material;
3) the molten 300ml THF of step enriched material .2), and triphenyl phosphorus (79.0g, 1.0eq), water (1.0eq), RT stir and to spend the night, next day concentrated solvent, add pure sherwood oil and separate out a large amount of solids, filter, filtrate evaporating column chromatographic separation is purified, use methanol solvate then, (62g's Anhydrous potassium carbonate 1.5eq) refluxed 3 hours, concentrate, use water dissolution, use ethyl acetate extraction then, the dry extraction liquid that concentrates gained gets product (formula 14) 40.1g, total recovery 49.8%.
4) .N
2Protection;-5 ℃ of THF solution that slowly drip borine (2.0eq) down are in 3) go on foot in the dry THF solution of products obtained therefrom (formula 14); stirred overnight at room temperature finishes; next day, ice bath dripped the methyl alcohol cancellation down, was spin-dried for washing; dichloromethane extraction; dry concentrating adds a small amount of normal hexane and separates out white solid and be formula 16, and productive rate is 85%.
It below is formula 14
1H NMR and MS-ESI spectral data:
1H?NMR(300MHz,CDCl
3)δ1.42(s,9H);1.77~1.80(br,4H);2.89(s,1H);2.96(s,1H)3.13~3.22(br,2H);3.28~3.30(br,2H);3.81~3.85(br,2H);5.85~5.87(br,1H)ppm。
MS-ESI:cal.268.2;found:269.2(M+H)
+,291.3(M+Na)
+.
It below is formula 16
1H NMR and MS-ESI spectral data:
1H?NMR(300MHz,CDCl
3)δ1.26~1.44(br,3H);1.46(s,9H);1.55~1.72(br,5H);1.86~1.90(br,1H);2.31~2.51(br,1H);2.94~3.92(br,6H)ppm。MS-ESI:cal.254.2;found:255.3(M+H)
+.
Embodiment 2 (preparation of formula 24)
1) .N
2Protection,-15 ℃ drip LDA 300ml (0.6mol, 2.0eq) to 4-Boc piperidine ethyl formate (formula 21) (77g, 0.3mol) dry THF (200ml) solution in, finish and continue the low temperature stirring after 1 hour, with reaction solution under-15 ℃, be added drop-wise to 100ml 1-bromo-2-monochloroethane (formula 25) (86.0g, in dry THF solution 2.0eq), finishing slowly is warming up to RT and stirs and to spend the night; Add aqueous ammonium chloride solution next day and handle, revolve THF after, water is with ethyl acetate extraction 3 times, dry concentrating, enriched material;
2) .1) go on foot enriched material and be dissolved in 250ml DMF, add NaN in batches
3(40.0g, 2.0eq), N
2Protect following 50 ℃~60 ℃ stirrings to spend the night, next day, pure petroleum ether extraction was 3 times, merged the organic phase washing, and dry concentrating gets enriched material;
3) .2) go on foot enriched material and be dissolved in 300ml THF, and triphenyl phosphorus (79.0g, 1.0eq), water (1.0eq), RT stir and spend the night, and remove solvent next day, add pure sherwood oil and separate out a large amount of solids, filter, and filtrate evaporating column chromatographic separation is purified; Use methanol solvate then, (62g's Anhydrous potassium carbonate 1.5eq) refluxed 2 hours, concentrated, and used water dissolution, used ethyl acetate extraction then, and dry concentrated extract gets product 42.2g, total recovery 55.3%.
It below is formula 24
1H NMR and MS-ESI spectral data:
1H?NMR(300MHz,CDCl
3)δ1.35~1.47(br,11H);1.81~1.91(br,2H);2.01~2.11(br,2H);2.96~3.05(br,2H)3.35~3.39(br,2H);3.99~4.01(br,2H);5.91~5.92(br,1H)ppm。MS-ESI:cal.254.2;found:277.2(M+Na)
+.
Embodiment 3 (preparation of formula 34)
1) .N
2Protection, under-15 ℃ of conditions, drip LDA 300ml (0.6mol, 2.0eq) to 3-Boc piperidine methyl formate (formula 31) (77g, 0.3mol) dry THF (200mL) solution in, finish and continue low temperature and stir after 1 hour, reaction solution is being added drop-wise to 100ml 1-bromo-3-chloropropane (formula 35) (95.0g below-15 ℃, 2.0eq) dry THF solution in, finishing slowly is warming up to RT and stirs and to spend the night; Add aqueous ammonium chloride solution next day and handle, revolve THF after, water, ethyl acetate extraction 3 times, dry concentrating obtains enriched material;
2) .1) go on foot enriched material and be dissolved in 250ml DMF, add NaN in batches
3(40.0g, 2.0eq), N
2Protect following 50 ℃~60 ℃ stirrings to spend the night, next day, pure petroleum ether extraction was 3 times, merged the organic phase washing, and dry concentrating gets enriched material;
3) .2) go on foot enriched material and be dissolved in 300mlTHF, and triphenyl phosphorus (79.0g, 1.0eq), water (1.0eq), RT stir and spend the night, and remove solvent next day, add pure sherwood oil and separate out a large amount of solids, filter, and filtrate evaporating column chromatographic separation is purified; Use methanol solvate then, (62g's Anhydrous potassium carbonate 1.5eq) refluxed 5 hours, concentrated, and used water dissolution, used ethyl acetate extraction then, and dry concentrated extract gets product 38g, total recovery 47.2%.It below is formula 34
1H NMR and MS-ESI spectral data:
1H?NMR(300MHz,CDCl
3)δ1.55(s,9H);1.58~1.97(m,7H);2.12~2.18(m,1H);2.65~2.88(br,1H)3.10(br,1H);3.29(br,2H);3.97~4.01(m,2H);6.04~6.05(br,1H)ppm。MS-ESI:cal.268.2;found:269.2(M+H)
+,291.3(M+Na)
+.
Embodiment 4 (preparation of formula 44)
1) .N
2Protection, under-15 ℃ of conditions, drip LDA 300ml (0.6mol, 2.0eq) to 3-Boc piperidine methyl formate (formula 41) (77g, 0.3mol) dry THF (200mL) solution in, finish and continue low temperature and stir after 1 hour, reaction solution is being added drop-wise to 100ml 1-bromo-2-monochloroethane (formula 45) (86.0g below-15 ℃, 2.0eq) dry THF solution in, finishing slowly is warming up to RT and stirs and to spend the night; Add aqueous ammonium chloride solution next day and handle, revolve THF after, water, ethyl acetate extraction 3 times, dry concentrating obtains enriched material;
2) .1) go on foot enriched material and be dissolved in 250ml DMF, add NaN in batches
3(40.0g, 2.0eq), N
2Protect following 50 ℃~60 ℃ stirrings to spend the night, next day, pure petroleum ether extraction was 3 times, merged the organic phase washing, and dry concentrating obtains enriched material;
3) .2) go on foot enriched material and be dissolved in 300ml THF, and triphenyl phosphorus (79.0g, 1.0eq), water (1.0eq), RT stir and spend the night, and remove solvent next day, add pure sherwood oil and separate out a large amount of solids, filter, and filtrate evaporating column chromatographic separation is purified; Use methanol solvate then, (62g's Anhydrous potassium carbonate 1.5eq) refluxed 5 hours, concentrated, and used water dissolution, used ethyl acetate extraction then, and dry concentrated extract gets product 40.0g, total recovery 52.2%.
It below is formula 44
1H NMR and MS-ESI spectral data:
1H?NMR(300MHz,CDCl
3)δ1.43(s,9H);1.53~1.93(m,5H);2.15~2.17(br,1H);2.73~2.87(br,2H)3.35~3.41(br,2H);3.85~4.16(br,2H);6.25~6.582(br,1H)ppm。MS-ESI:cal.268.2;found:269.2(M+H)
+,291.3(M+Na)
+.
Embodiment 5 (preparation of formula 54)
1) .N
2Protection, under-15 ℃ of conditions, drip LDA 300ml (0.6mol, 2.0eq) to N-Boc proline methyl ester (formula 51) (68.7g, 0.3mol) dry THF (200ml) solution in, finish and continue low temperature and stir after 1 hour, reaction solution is being added drop-wise to 100ml 1-bromo-2-monochloroethane (formula 55) (86.0g below-15 ℃, 2.0eq) dry THF solution in, finishing slowly is warming up to RT and stirs and to spend the night; Add aqueous ammonium chloride solution next day and handle, revolve THF after, water, ethyl acetate extraction 3 times, dry concentrating obtains enriched material;
2) .1) go on foot enriched material and be dissolved in 250ml DMF, add NaN in batches
3(40.0g, 2.0eq), N
2Protect following 50 ℃~60 ℃ stirrings to spend the night, next day, pure petroleum ether extraction was 3 times, merged the organic phase washing, and dry concentrating obtains enriched material;
3) .2) go on foot enriched material and be dissolved in 300mlTHF, and triphenyl phosphorus (79.0g, 1.0eq), water (1.0eq), RT stir and spend the night, and remove solvent next day, add pure sherwood oil and separate out a large amount of solids, filter, and filtrate evaporating column chromatographic separation is purified; Use methanol solvate then, (62g's Anhydrous potassium carbonate 1.5eq) refluxed 5 hours, concentrated, and used water dissolution, used ethyl acetate extraction then, and dry concentrated extract gets product 42.0g, total recovery 55.1%.
It below is formula 54
1H NMR and MS-ESI spectral data:
1H?NMR(300MHz,CDCl
3)δ1.43(s,9H);1.75~2.00(br,6H);2.25~2.32(br,2H);3.30~3.32(br,1H)3.50~3.59(br,3H);5.85~6.18(br,1H)ppm。MS-ESI:cal.254.2;found:155.1(M+H-Boc)
+,277.2(M+Na)
+
Embodiment 6 (preparation of formula 64)
1) .N
2Protection, under-15 ℃ of conditions, drip LDA300ml (0.6mol, 2.0eq) to N-Boc-proline methyl ester (formula 61) (68.7g, 0.3mol) dry THF (200ml) solution in, finish and continue low temperature and stir after 1 hour, reaction solution is being added drop-wise to 100ml 1-bromo-2-monochloroethane (formula 65) (86.0g below-15 ℃, 2.0eq) dry THF solution in, finishing slowly is warming up to RT and stirs and to spend the night; Add aqueous ammonium chloride solution next day and handle, revolve THF after, water, ethyl acetate extraction 3 times, dry concentrating obtains enriched material;
2) .1) go on foot enriched material and be dissolved in 250ml DMF, add NaN in batches
3(40.0g, 2.0eq), N
2Protect following 50 ℃~60 ℃ stirrings to spend the night, next day, pure petroleum ether extraction was 3 times, merged the organic phase washing, and dry concentrating obtains enriched material;
3) .2) go on foot enriched material and be dissolved in 300mlTHF, and triphenyl phosphorus (79.0g, 1.0eq), water (1.0eq), RT stir and spend the night, and remove solvent next day, add pure sherwood oil and separate out a large amount of solids, filter, and filtrate evaporating column chromatographic separation is purified; Use methanol solvate then, (62g's Anhydrous potassium carbonate 1.5eq) refluxed 5 hours, concentrated, and used water dissolution, used ethyl acetate extraction then, and dry concentrated extract gets product 39.0g, total recovery 54.2%.
It below is formula 64
1HNMR and MS-ESI spectral data:
1H?NMR(300MHz,CDCl
3)δ1.48(s,9H);1.82~2.02(br,4H);2.09~2.19(br,1H);2.59~2.76(m,1H)3.24~3.57(m,4H);5.82~5.98(br,1H)ppm。MS-ESI:cal.240.2;found:141.1(M+H-Boc)
+,263.2(M+Na)
+
Embodiment 7 (preparation of formula 75)
1) .N
2Protection, under-15 ℃ of conditions, drip LDA 300ml (0.6mol, 2.0eq) to 2-Boc piperidine ethyl formate (formula 71) (77g, 0.3mol) dry THF (200ml) solution in, finish and continue low temperature and stir after 1 hour, reaction solution is being added drop-wise to 100ml 1-bromine 3-chloropropane (formula 75) (95.0g below-15 ℃, 2.0eq) dry THF solution in, finishing slowly is warming up to RT and stirs and to spend the night; Add aqueous ammonium chloride solution next day and handle, revolve THF after, water, ethyl acetate extraction 3 times, dry concentrating obtains enriched material;
2) .1) go on foot enriched material and be dissolved in 250ml DMF, add NaN in batches
3(40.0g, 2.0eq), N
2Protect following 50 ℃ of-60 ℃ of stirrings to spend the night, next day, pure petroleum ether extraction was 3 times, merged the organic phase washing, and dry concentrating obtains enriched material;
3) the molten 300ml THF of step enriched material .2), and triphenyl phosphorus (79.0g, 1.0eq), water (1.0eq), RT stir and spend the night, and remove solvent next day, add pure sherwood oil and separate out a large amount of solids, filter, and filtrate evaporating column chromatographic separation is purified; Use methanol solvate then, (62g's Anhydrous potassium carbonate 1.5eq) refluxed 5 hours, concentrated, and used water dissolution, used ethyl acetate extraction then, and dry concentrated extract gets product 40.0g, total recovery 52.2%.
It below is formula 64
1H NMR and MS-ESI spectral data:
1H?NMR(300MHz,CDCl
3)δ1.46(s,9H);1.52~2.01(m,9H);2.12~2.16(brs,1H);2.99~3.03(br,2H);3.21~3.25(br,1H);3.86~3.90(br,1H);5.85~6.05(br,1H)ppm。MS-ESI:cal.268.2;found:169.2(M+H-Boc)
+,291.3(M+Na)
+
Should be pointed out that R
1Effect in the present invention is a blocking group, and those skilled in the art can expect to obtain the present invention to R
1The qualification group all can not hinder the carrying out of each step reaction of the present invention, therefore, here no longer to various R
1Related embodiment does one by one and enumerates.
Claims (8)
1. method for preparing diazaspiracyclic compounds, described diazaspiracyclic compounds has the structure of formula I or formula VI, and this method is an initial feed with compound formula V, comprising:
A, spend proton reagent and slough in the compound formula V hydrogen on the position No. 1, then carry out alkylated reaction, form the first intermediate product formula II with the halogenated saturated chain alkane formula III in two ends;
B, replace in the first intermediate product formula II halogen X on the carbon of position No. 2 with azide reagent
2, form the second intermediate product formula IV;
C, the second intermediate product formula IV is reduced ring closure reaction, form diazaspiracyclic compounds formula I;
D, diazaspiracyclic compounds formula I reduced obtain diazaspiracyclic compounds formula VI;
R wherein
1Be hydrogen, the alkyl that contains 1-6 carbon, tertbutyloxycarbonyl, carbobenzoxy-(Cbz) or benzyl;
R
2For containing the alkyl of 1-6 carbon;
X is an oxygen; X
1Be chlorine, bromine or iodine; X
2Be chlorine, bromine or iodine; Described X
1Reactive behavior more than or equal to X
2Reactive behavior;
M is 1,2 or 3, and n is 0,1,2 or 3, and during m=1, n ≠ 0; Y is 1,2 or 3; P is 1,2 or 3.
2. a kind of method for preparing diazaspiracyclic compounds according to claim 1, it is characterized in that the reduction ring closure reaction in the described c step is that the second intermediate product formula IV is reacted with triphenyl phosphorus in organic solvent, described organic solvent is a kind of in acetate, THF, methyl alcohol or the ethanol, and temperature of reaction is 15~50 ℃.
3. a kind of method for preparing diazaspiracyclic compounds according to claim 1 and 2 is characterized in that azide reagent is sodiumazide in the described b step, and described organic solvent is DMF or acetone, and temperature of reaction is 25~85 ℃.
4. a kind of method for preparing diazaspiracyclic compounds according to claim 3, the deprotonation reagent that it is characterized in that described a step is lithium diisopropylamine, and temperature of reaction is-30~-5 ℃, and reaction solvent is THF.
5. a kind of method for preparing diazaspiracyclic compounds according to claim 3, it is characterized in that described d step diazaspiracyclic compounds formula I is carried out the reductive reductive agent is lithium aluminium hydride or borine.
6. ask 2 described a kind of methods that prepare diazaspiracyclic compounds according to right, it is characterized in that the mol ratio of the triphenyl phosphorus and second intermediate product formula IV input reaction is 1.0~2.0: 1.0.
7. ask 3 described a kind of methods that prepare diazaspiracyclic compounds according to right, it is characterized in that the reaction input mol ratio of the sodiumazide and the first intermediate product formula II is 1.5~2.0: 1.0.
8. ask 4 described a kind of methods that prepare diazaspiracyclic compounds according to right, the reaction input mol ratio that it is characterized in that lithium diisopropylamine and compound formula V is 1.2-3.0: 1.0, and it is 1.2-3.0 that the reaction of halogenated saturated chain alkane formula III in two ends and compound formula V drops into mol ratio: 1.0.
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