CN102442934A - Synthetic method of 6-oxo-2-azaspiro[3,3]heptane-2-t-butyl carboxylate - Google Patents

Abstract

The invention relates to the chemical synthesis field, and concretely relates to a synthetic method of 6-oxo-2-azaspiro[3,3]heptane-2-t-butyl carboxylate. The synthetic method is characterized in that the synthetic method comprises the following steps: 1, reducing a raw material compound (14) with lithium aluminum hydride; 2, selecting Ts (toluene sulfonyl) protection; 3, carrying out ring closure on the substance obtained in step 2 and o-nitrobenzenesulfonamide under the action of potash to obtain a compound (19); 4, reacting the compound (19) with thiophenol in a solvent DMF (dimethylformamide) under the action of potash to obtain a compound (20); and 5, generating a ketone under acidic conditions, and reacting the ketone with BOC2O (di-tert-butyl dicarbonate) under alkaline conditions to obtain 6-oxo-2-azaspiro[3,3]heptane-2-t-butyl carboxylate. The preparation method of the invention, which allows the yield to be high, the whole yield to reach 41% and conditions to be mild, is a synthetic method with large scale preparation values.

Description

The compound method of 6-oxo-2-azaspiro [3,3] heptane-2-carboxylic acid tert-butyl ester

Technical field

The present invention relates to the field of chemical synthesis, be specifically related to the compound method of 6-oxo-2-azaspiro [3,3] heptane-2-carboxylic acid tert-butyl ester.

Background technology

The quasi-medicated property chemical structure analysis shows recently, and quite few structural framing has occupied most so-called Chemical Diversity space.Molecule lacks the possibility that structure diversity has limited the novel lead compound in the discovery new drug development in the compound library.Therefore, need to seek novel structure, be easy to the synthetic construction module and be used for novel drug effect functional group.In about 1350 small-molecule drug of FDA approval, have piperidine ring in 137,73 have piperazine ring.The similar surrogate of finding piperidines and piperazine provides possibility for expanding quasi-medicated property chemical space and variety.In fact, 2,6-diaza spiro [3.3] heptane has caused strong interest as the surrogate of piperazine ring at medicine industry.Though 2,6-diaza spiro [3.3] heptane is at the focus that is reported that and becomes the organic synthesis field of the 1830's, the piperazine ring surrogate that has dual-use functionization accordingly has only a small amount of report.And the 6-oxo-2-azaspiro [3.3] heptane-the 2-carboxylic acid tert-butyl ester is a Synthetic 2, the midbody of the key of 6-diaza spiro [3.3] heptane.

For 6-oxo-2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester preparation, bibliographical information related compound method is following:

Method is by Org.Lett., Vol.11, and No.163523-3525 reports two synthetic routes, as follows:

Reagent and productive rate: (I) 76% (II) ethyl cyanoacetate, K ₂CO ₃, N, dinethylformamide (DMF), 55%; (III) NaBH ₄, 95%; (IV) Tosyl chloride (TsCl), triethylamine (TEA), 4-Dimethylamino pyridine (DMAP), 91%; (V) LiAlH ₄(VI) tert-Butyl dicarbonate (BOC ₂O), 82%; (VII) Pd (OH) ₂, 90%; (VIII) Dai Si-Martin's oxygenant (DMP), 72%.

Reagent and productive rate: (IX) Ph ₃PCH ₃Br, potassium tert.-butoxide, 52%; (X) trichoroacetic chloride, Zn; (XI) Zn, AcOH, 40% (two steps).

Not enough below the compound method of this report exists: the first method step is long: 8 steps, total recovery: 19%; Second method total recovery: 21%.The shortcoming that overall yield is low does not possess the feasibility of mass preparation.

In addition, bibliographical information synthetic (Amino Acids (2010) 39:515-521) of compound 17, compound 15 (Tetrahedron:Asymmetry, 19 (24), 2924-2930; 2008) as follows:

Reagent and productive rate: (XII) NaH, NSC 406716,56%; (XIII) LiAlH ₄, 74%; (XIV) MsCl, triethylamine (TEA), 100%; (X V) TsNH ₂, K ₂CO ₃, 59%.

In addition, US2009/0233903A1 has also reported the synthetic of compound (16)

Reagent and productive rate: (XIII) LiAlH ₄, 89%; (XIV) methylsulfonyl chloride (MsCl), TEA, 95.4%.

Bibliographical information synthetic (Tetrahedron:Asymmetry, 19 (24), the 2924-2930 of compound (18); 2008) as follows:

Reagent and productive rate: (XVI) TsCl, pyridine, 80%.

Not enough below more than the compound method of report exists: the yield of compound (15) is not very high, and the yield of compound (17) is very low, is not suitable for the feasibility of mass preparation.

Summary of the invention

The purpose of this invention is to provide a kind of efficient, compound method of possessing 6-oxo-2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester that mass preparation is worth.Solve mainly that existing the 6-oxo-heptane-2-carboxylic acid tert-butyl ester yield is low for 2-azaspiro [3.3], midbody is difficult to purifying, technical problem that can't scale operation.

Concrete compound method of the present invention is following:

Wherein respectively go on foot reaction conditions:

XVII: add the lithium aluminum hydride reduction reaction;

XVIII: add Tosyl chloride, solvent is a pyridine;

XIX: add ortho-nitrophenyl sulphonamide and salt of wormwood;

XX: add thiophenol and salt of wormwood;

XXI: add acid and become ketone, transfer alkalescence to add tert-Butyl dicarbonate again.

Wherein in the XVII step, the preferred THF of solvent; Preferred 0～20 ℃ of temperature of reaction; The mol ratio of raw material (14) and lithium aluminum hydride is preferred: 1: 1.0～1: 1.5.

In the XIX step, the preferred methyl-sulphoxide of solvent; Preferred 90～120 ℃ of temperature of reaction.

In the XX step, the preferred N of solvent, dinethylformamide.

In the XXI step, solvent ethyl acetate (EA).

In the XXI step, the preferred hydrochloric acid of acid; The preferred sodium hydrogencarbonate of alkali.

The present invention is raw material with the first step with compound (14), and lithium aluminium hydride reduction, solvent for use are THF or ether, and reaction obtains compound (15), and yield can reach 96.2%; Second step was selected the Ts protection; In the 3rd step, under the salt of wormwood effect, close ring with the ortho-nitrophenyl sulphonamide and obtain compound (19); The 4th step compound (19) is a solvent with DMF under the salt of wormwood effect, obtains compound (20) with the thiophenol reaction; The 5th step is generation ketone under acidic conditions, under alkaline condition and BOC ₂O, reaction obtains 6-oxo-2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester.

We had once attempted making and have sloughed Ts again behind the compound (17) and get compound (20), but severe reaction conditions.This reaction needed is under the UW condition, and methyl alcohol is the reaction of solvent and magnesium powder, dashes material easily, can not mass preparation; Perhaps strong alkaline condition refluxed reaction, condition is violent, can't tolerate.

Reaction process of the present invention is reasonable in design, is raw material with compound (14), lithium aluminium hydride reduction; Encircle and remove the protection base in condition ShiShimonoseki of gentleness then, preparing method's productive rate of the present invention is high, and total recovery can reach 41%; And mild condition is a kind of compound method that mass preparation is worth that possesses.

The practical implementation method

Embodiment 1

Synthesizing of compound (15)

105g (2.749mol, 1.5eq) lithium aluminum hydride is suspended among the 4000mL THF, lower the temperature 0 ℃, Dropwise 5 28g compound (14) (1.931mol, 1.0eq)/1000mL THF, temperature control is no more than 20 ℃, drips complete stirring at room 30min, and TLC does not have raw material.Carefully in reaction solution, drip 105mL water, 105mL 15% sodium hydroxide solution, 105mL water filters, and filter cake washes twice with THF, boils off solvent and gets yellow liquid 310g, drops into next step reaction.Yield 96.2%. ¹H?NMR(400MHz，CDCl3)δ(ppm)3.69(s，4H)，3.32(s，2H)，3.13(s，6H)，1.94(s，4H)。

Synthesizing of compound 18

(2.838mol 1.0eq) is dissolved in the 2500mL pyridine compound (15) 500g, and add 1623g TsCl (8.513mol, 3.0eq), the added-time controlled temperature is no more than 20 ℃, finishes stirred overnight at room temperature in batches.Reaction solution is poured in the 6L water, stirs, and has the off-white color solid to separate out, and filtering drying gets off-white color solid 1050g, drops into next step reaction.Yield 80%.

Synthesizing of compound (19)

Compound (18) 1000g (2.064mol, 1.0eq), 460g (2.27mol; 1.1eq) the ortho-nitrophenyl sulphonamide, 146g (10.3mol, 5.0eq) salt of wormwood; 4.5L methyl-sulphoxide (DMSO) drops in the 10L four-hole bottle, heats 100～110 ℃ of reaction 4h, TLC monitoring raw material reaction is complete.Reaction solution is poured in the 7L water, EA 5L, and 4L, 3L extracts, and merges organic phase brine wash (5L * 3), and drying boils off solvent and gets yellow solid, with sherwood oil (PE) wash solids,, obtain yellow solid 625g, directly drop into next step reaction.Bullion yield 88.5%.

Synthesizing of compound (20)

Compound (19) 625g (1.826mol, 1.0eq), 242g (2.191mol, 1.2eq) thiophenol, 505g (3.652mol, 2.0eq) salt of wormwood, 3L DMF drop in the single port bottle, stirred overnight at room temperature, TLC does not have raw material.Reaction solution is poured in the 4L water, and EA (3L * 2) extracts, and water directly drops into next step reaction.

Synthesizing of compound (9)

The aqueous solution of compound (20) is regulated pH to 1 with hydrochloric acid, and stirred overnight at room temperature is transferred alkalescence with the yellow soda ash solid again, adds 398g (1.826mmol, 1.0eq) Boc ₂O, 2L ETHYLE ACETATE, sodium hydrogencarbonate 230g (2.738mol, 1.5eq), stirred overnight at room temperature.Separatory, water extracts (3L * 2) with EA, merges salt washing (3L * 2), and drying boils off solvent, adds the PE recrystallization and gets white solid 231.8g.Two step total recoverys 60.1%, purity 99%. ¹HNMR(CDCl3，400MHZ)δ4.15(s，4H)，3.31(s，4H)，1.47(s，9H)。

Claims (6)

1. the preparation method of a compound (9) comprising:

Wherein respectively go on foot reaction conditions:

XVII: add the lithium aluminum hydride reduction reaction;

XVIII: add Tosyl chloride, solvent is a pyridine;

XIX: add ortho-nitrophenyl sulphonamide and salt of wormwood;

XX: add thiophenol and salt of wormwood;

XXI: add acid and become ketone, transfer alkalescence to add tert-Butyl dicarbonate again.

2. the preparation method of claim 1, wherein in the XVII step, solvent is a THF; Temperature of reaction is 0～20 ℃; The mol ratio of raw material (14) and lithium aluminum hydride is: 1.0: 1.0～1.0: 1.5.

3. the preparation method of claim 1, wherein in the XIX step, solvent is a methyl-sulphoxide; Temperature of reaction is 90～120 ℃.

4. the preparation method of claim 1, wherein in the XX step, solvent is N, dinethylformamide.

5. the preparation method of claim 1, wherein in the XXI step, solvent is an ETHYLE ACETATE.

6. the preparation method of claim 1, wherein in the XXI step, acid is hydrochloric acid; Alkali is sodium hydrogencarbonate.