CN104045593B

CN104045593B - A kind of preparation method of trandolapril intermediate

Info

Publication number: CN104045593B
Application number: CN201310079006.8A
Authority: CN
Inventors: 张万斌; 刘德龙; 申杰峰; 时涛
Original assignee: Shanghai Jiaotong University
Current assignee: Shanghai Jiaotong University
Priority date: 2013-03-12
Filing date: 2013-03-12
Publication date: 2016-11-02
Anticipated expiration: 2033-03-12
Also published as: CN104045593A

Abstract

The present invention relates to the preparation method of a kind of trandolapril intermediate, it may be assumed that by cyclohexene and toluene-sodium-sulfonchloramide be initiation material reaction obtain hexamethylene ethylene imine；Hexamethylene ethylene imine and pi-allyl grignard reagent react and obtain trans N to Methyl benzenesulfonyl base 2 (2 acrylic) cyclohexylamine; and under the effect of oxidant, obtain the N of trans DL to Methyl benzenesulfonyl base octahydro 1H indoles 2 formic acid; the free carboxyl of esterification protection obtains the N of trans DL to Methyl benzenesulfonyl base octahydro 1H indoles 2 methyl formate; after sloughing the Ts protection group on nitrogen and hydrolysis, obtain octahydro 1H indoles 2 benzyl formate of trans DL through benzyl esterification.Separated, fractionation again obtains trandolapril key intermediate (2S, 3aR, 7aS) octahydro 1H indoles 2 benzyl formate.Raw material of the present invention is cheap and easy to get, and preparation process is environmentally friendly, and operation and post processing are simple.

Description

A kind of preparation method of trandolapril intermediate

Technical field

The present invention relates to biomedicine field, particularly relate in cardiovascular drugs with regard in the key of Trandolapril The brand-new preparation method of mesosome.

Background technology

Trandolapril (Trandolapril), chemistry is entitled: (2S, 3aR, 7aS)-[(2S)-[(1S)-(carbethoxyl group)- Phenyl propyl] amino }]-propiono]-octahydro-1H-indole-2-carboxylic acid, developed by Roussel Uclaf company of France. Be a kind of long-acting vasotonia converting enzyme inhibitor, multiple angiocardiopathy can be treated, have evident in efficacy, The advantages such as long action time, side effect are little.Further investigation revealed that Trandolapril can be effectively improved blood pressure normal The peripheral neuropathy of diabetes patient.

The main part of Trandolapril structure and a lot of vasotonia converting enzyme inhibitor (such as enalapril) phases With, the different side chains being that them, when therefore preparing Trandolapril, its side chain (2S, 3aR, 7aS)- The synthesis of octahydro-1H-indole-2-carboxylic acid and benzyl ester thereof is crucial.At present, the synthetic route of this carboxylic acid and benzyl ester thereof There is the shortcomings such as with high costs, complex operation, it is impossible to large-scale production.

Patent US6599318 uses enzyme process to carry out three-dimensional synthesis, but high cost, reaction condition is extremely harsh, Be not suitable for industrialized production.Document report with the racemic octahydro-1H-indole-2-carboxylic acid of advantage of lower cost with Parent is separated by post after connecting, and crude product can get highly purified individual isomer through recrystallizing, therefore (2 β, 3a β, 7a α)-octahydro-1H-indole-2-carboxylic acid become synthesis Trandolapril an important intermediate.In addition other documents The method of report there is also some shortcomings, such as Henning R, Urbach H. (Tetrahedron Lett., 1983, 24 (48), 5343-5346.) although the step using is less, but employ mercuric nitrate, it is unfavorable for environmental protection, it is also possible to Bring the impurity of cis-configuration into；Patented method [US4933361] with cyclohexanone as initiation material, selective hydrogen Change a step to be difficult to control to, and impurity is not readily separated；The trans hydrogenation of initiation material that patent [US4879392] is reported Isobenzofuranone is difficult to obtain；Patent [WO054194] employs more expensive reagent, high cost. WO2006014916 discloses the method that one prepares (2S, 3aR, 7aS)-octahydro-1H-indole-2-carboxylic acid, adopts With barium hydroxide octahydrate as catalyst, solvent is water, and reaction temperature is 107 DEG C, and the reaction time is the shortest is 4h.Costly, and the reaction time is longer, uses ethanol in last handling process for said method used catalyst Extract emulsification serious, occur that pole is difficult to suction filtration phenomenon, yield relatively low (32%), cause the cost of target product relatively High.Patent [US20070225505] have employed cheap and easily-available cyclohexene and chloramine-T is initiation material, but its In have employed costliness reagent, relatively costly；Patent [CN101597254A] is at patent [US20070225505] On the basis of be optimized, but still there is the shortcoming that route is longer and operation is complicated.

Publication No. 102887853A, the Chinese patent application of Application No. 201110206939.X provide one The preparation method of trandolapril intermediate, all obtains trans a pair of horses going side by side when one of this dominance of strategies is exactly oxidative cyclization Ring product amino alcohol, substantially increases the combined coefficient of Trandolapril.But, this technique there is also some needs Improved place: 1) raw material N-p-toluenesulfonyl-7-azabicyclic [4.1.0] heptane is more expensive in this route, if Changing and synthesizing this compound with cyclohexene for initiation material in advance, synthesis cost will reduce further.2) synthesize The protection group removing in route on N separates with naphthalene sodium as reagent and through resin column, synthesizes small, And operate cumbersome.3) synthesis technique need further to optimize, to reduce the poisonous use having pollution reagent And improve the total recovery of reaction.

In sum, the preparation method of existing (2S, 3aR, 7aS)-octahydro-1H-indole-2-carboxylic acid and benzyl ester thereof There is process route long, the shortcomings such as operation is complicated, and use a large amount of poisonous and harmful, expensive reagent, Cost is high, and gross production rate is low, is unfavorable for environmental protection and large-scale production.For above-mentioned deficiency, we intend to original work Make to carry out the improvement of synthetic route and the optimization of synthesis technique, (2S, 3aR, 7aS)-octahydro-1H-Yin is provided Diindyl-2-benzyl formate can the approach of industrialized production.

Content of the invention

The purpose of the present invention is contemplated to the defect overcoming above-mentioned prior art to exist, a kind of rational technology of offer, The preparation method of trandolapril intermediate simple to operate, with low cost.

The purpose of the present invention can be achieved through the following technical solutions:

The preparation method of a kind of trandolapril intermediate of the present invention, trandolapril intermediate refers to that how general group is Key intermediate (2S, 3aR, the 7aS)-octahydro-1H-indole-2-carboxylic acid benzyl ester of profit, its structure is as follows:

Described preparation method particularly as follows:

The first step, is that initiation material reaction obtains hexamethylene ethylene imine by cyclohexene and chloramine-T；

Second step, hexamethylene ethylene imine and allylic bromination reactive magnesium obtain trans-N-to Methyl benzenesulfonyl base -2-(2-acrylic)-cyclohexylamine；

3rd step, trans N-to Methyl benzenesulfonyl base-2-(2-acrylic)-cyclohexylamine under the effect of oxidant Obtain the N-of trans DL to Methyl benzenesulfonyl base-octahydro-1H-indole-2-carboxylic acid；

4th step, the N-of trans DL carries out esterification guarantor to Methyl benzenesulfonyl base-octahydro-1H-indole-2-carboxylic acid Protect carboxyl and obtain the N-of DL to Methyl benzenesulfonyl base-octahydro-1H-indole-2-ethyl formate；

5th step, the N-of trans DL to Methyl benzenesulfonyl base-octahydro-1H-indole-2-ethyl formate through sloughing nitrogen Upper p-toluenesulfonyl obtains the octahydro-1H-indole-2-ethyl formate of trans DL；

6th step, the octahydro-1H-indole-2-ethyl formate of trans DL obtains the octahydro of trans DL through hydrolysis -1H-indole-2-carboxylic acid；

The reaction of 7th step, the octahydro-1H-indole-2-carboxylic acid of trans DL and benzylalcohol obtains the octahydro-1H-of DL Indole-2-carboxylic acid benzyl ester；

8th step, the octahydro-1H-indole-2-carboxylic acid benzyl ester of trans DL separates through recrystallization, splits that to obtain group many Puli's key intermediate (2S, 3aR, 7aS)-octahydro-1H-indole-2-carboxylic acid benzyl ester.

In above step:

Preferably, in the first step, the mol ratio of described chloramine-T and cyclohexene is 1:1～1:10, the two reaction Catalyst includes I2, N-bromo-succinimide, N-bromo acetamide and phase transfer catalyst (tetrabutyl iodate Ammonium, TBAB, tetrabutylammonium chloride, tetramethyl-ammonium iodide, 4 bromide, tetramethyl chlorination Ammonium, benzyltrimethylammonium bromide, benzyltrimethylammonium chloride, benzyltriethylammoinium chloride, tricaprylmethyl chlorine Change the phase transfer catalyst that can be used for this reaction used by ammonium, DTAC etc.), catalyst with The mol ratio of chloramine-T is 1:20～1:50, and the solvent of reaction can be for including: oxolane, ether, dichloro Methane, chloroform, acetonitrile, toluene, methyl alcohol, ethanol, isopropanol, DMF, DMSO etc. are all be can be used for The polarity of this reaction and non-polar solven.

Preferably, in second step, in described hexamethylene ethylene imine and allylic bromination reactive magnesium: allyl bromide, bromoallylene The mole dosage changing azoviolet is 5 times of hexamethylene ethylene imine, and this reaction used catalyst includes copper chloride, chlorine Change cuprous, copper bromide, cuprous bromide, cupric iodide, cuprous iodide, trifluoromethayl sulfonic acid copper, TFMS Can be used for any one in the catalyst of this reaction used by cuprous, cuprous bromide dimethyl sulphide etc., preferably copper bromide, Catalyst is 1:10～1:100 with the mol ratio of allylic bromination magnesium, and reaction is carried out at-78 DEG C～50 DEG C, excellent Temperature is selected to be-40 DEG C.

Preferably, in the 3rd step, in described oxidation reaction: solvent includes acetonitrile, oxolane, ether, Dichloromethane, chloroform, acetonitrile, toluene, methyl alcohol, ethanol, isopropanol, DMF, DMSO, carbon tetrachloride, Acetone-waters etc. can be used for the one in the conventional organic solvent of this reaction, and solvent load is 100mL～5000mL/ Mole, it is oxidized to trans octahydro-1H-indole-2-carboxylic acid, reaction temperature is-30 DEG C～50 DEG C, and preferable temperature is -5℃。

It is highly preferred that described oxidant includes: ozone, hydrogen peroxide, Peracetic acid, benzoyl hydroperoxide, Chloroperoxybenzoic acid, potassium permanganate, chromium trioxide, red fuming nitric acid (RFNA), trifluoro Peracetic acid, sodium chlorite, secondary chlorine All any one oxidants that can be used for this reaction, preferably m-chloro such as acid sodium, sym-closene, sodium metaperiodate Perbenzoic acid.

It is highly preferred that the catalyst of described oxidation reaction includes: 2,2,6,6-tetramethyl piperidines-nitrogen-oxide, bromine Change sodium, KBr, sodium chloride, potassium chloride, sodium fluoride, potassium fluoride, lithium fluoride, TBAB, water Close ruthenium trichloride, iron chloride hexahydrate.

Preferably, in the 4th step, carboxyl ester obtains the N-of trans DL to Methyl benzenesulfonyl base-octahydro-1H- Indole-2-ethyl formate.In described esterification reaction of organic acid, reagent be methyl alcohol, 2,2-dimethoxypropane, iodomethane, Dimethyl suflfate, diazomethane.Preferably methyl alcohol.

It is highly preferred that esterification condition used is methyl alcohol/acidic catalyst, 2,2-dimethoxypropane/acidity is urged Agent, iodomethane/alkali, dimethyl suflfate/alkali, diazomethane/acid.

It is highly preferred that described esterification reaction of organic acid acidic catalyst include sulfuric acid, hydrochloric acid, perchloric acid, to toluene sulphur Acid, benzene sulfonic acid, acetic acid, thionyl chloride, any one in fluoboric acid.

It is highly preferred that described esterification reaction of organic acid alkali includes NaOH, potassium hydroxide, barium hydroxide, hydroxide Calcium, described acid includes appointing in hydrochloric acid, sulfuric acid, benzene sulfonic acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, perchloric acid A kind of.

It is highly preferred that in described esterification reaction of organic acid, methyl esterification reagent with the molar feed ratio of raw material is 1:1～100:1, preferably 20:1.

It is highly preferred that described esterification reaction of organic acid temperature is 0 DEG C～100 DEG C, preferable temperature is reflux temperature.

Preferably, in the 5th step, the N-of trans DL is to Methyl benzenesulfonyl base-octahydro-1H-indole-2-carboxylic acid first Ester sloughs the octahydro-1H-indole-2-ethyl formate that p-toluenesulfonyl on nitrogen obtains trans DL, described sloughs nitrogen Upper p-toluenesulfonyl, reagent includes: naphthalene sodium, lithium naphthalene, magnesium powder, preferably magnesium powder.Described slough on nitrogen to first Benzenesulfonyl reaction dissolvent can be: any one of methyl alcohol, oxolane, preferably methyl alcohol.

It is highly preferred that described, to slough the reaction condition used by p-toluenesulfonyl on nitrogen be magnesium/methyl alcohol, sodium naphthalene/tetra- Hydrogen furans, lithium naphthalene/oxolane, reaction temperature is-80 DEG C～100 DEG C, and preferable temperature is 25 DEG C.

Preferably, in the 6th step, described methyl esters hydrolysing agent includes: hydrazine hydrate, ammoniacal liquor, NaOH, hydrogen Potassium oxide, lithium hydroxide, hydrochloric acid, preferably NaOH.Described hydrolysing agent and the octahydro-1H-of trans DL The molar ratio of indole-2-ethyl formate is 1:1～20:1.

It is highly preferred that described methyl esters hydrolysising solvent include in methanol-water, isopropanol-water, n-butanol-water any One, preferably methanol-water.Reaction temperature is 0 DEG C～100 DEG C, and preferable temperature is 25 DEG C.

Preferably, in the 7th step, described one-tenth benzyl ester reagent include: benzylalcohol, described solvent include methyl alcohol, methyl alcohol, Water, isopropanol, n-butanol, the tert-butyl alcohol, oxolane, ether, dichloromethane, acetonitrile, toluene, tetrachloro Changing any one of carbon, ethyl acetate, reaction temperature is 0 DEG C～100 DEG C.

Preferably, in the 8th step, described recrystallization, use solvent to include: ethanol, methyl alcohol, isopropanol, first Benzene, acetone, ethyl acetate, dichloromethane, chloroform, methyl tertiary butyl ether(MTBE), isopropyl ether, ether, petroleum ether, Pentamethylene, hexamethylene, cycloheptane, pentane, this crystallization process can be applied in the place such as n-hexane and normal heptane One of which or the mixed solvent appointing several solvents, be preferably the less solvent of polarity and these solvents carry out group Close and use.Recrystallization temperature-70 DEG C～50 DEG C, preferable temperature is 5 DEG C.

Preferably, described fractionation includes that resolving agent splits and chiral column splits:

1. resolving agent splits: resolution reagent includes: L-TARTARIC ACID, L-are to toluoyltartaric, L-hexichol first One in acyl tartaric acid, L-diacetyl tartaric acid, preferably L-is to toluoyltartaric, resolution reagent and DL The mol ratio of octahydro indole-2-carboxylic acid benzyl ester be: 0.5～1, resolution solvent consumption is 500mL-1000mL/ The octahydro indole-2-carboxylic acid benzyl ester of mole DL, temperature is carried out at-20 DEG C～30 DEG C.Resolution solvent includes: Acetonitrile, ethanol, isopropanol, ether, DMF, ethyl acetate, acetone, methyl tertiary butyl ether etc. are conventional organic Solvent or the mixture of these solvents.

2. prepared by chirality: suitable chiral preparatory column or routine are prepared post and be prepared at certain temperature and solvent To optically pure octahydro indole-2-carboxylic acid benzyl ester.Described temperature is 20 DEG C～40 DEG C, and described solvent includes: just Octane, isooctane, normal heptane, n-hexane, ethyl acetate, ethanol, methyl alcohol, isopropanol, the one of acetonitrile Or the mixed solvent of multi-solvents.

The route of the present invention is as follows:

In the present invention, the synthetic route of employing has the advantage that

1., in the presence of a catalyst, with cyclohexene and chloramine-T as initiation material, form hexamethylene ethylene imine, The crystal of available pure white, productivity is up to 95%, and solvent recoverable, and synthesis cost drops further Low.

2. hexamethylene ethylene imine and pi-allyl grignard reagent react, and obtain trans-N-to Methyl benzenesulfonyl base -2-(2-acrylic)-cyclohexylamine, productivity is up to 95%, and there is not the product of cis-configuration, direct construction two Individual chiral centre, has good stereoselectivity.

3. trans-N-can be efficient under the effect of oxidant to Methyl benzenesulfonyl base-2-(2-acrylic)-cyclohexylamine Obtaining the trans-N-of DL to Methyl benzenesulfonyl base-octahydro-1H-indole-2-carboxylic acid, this reaction condition is gentle, easily Operation, productivity is high, and solvent is recyclable to be directly utilized, simple to operate, mild condition, and product can be by recrystallization Obtain.

4. trans-the N-of DL is to Methyl benzenesulfonyl base-octahydro-1H-indole-2-carboxylic acid, under conditions of catalyst Obtain esterification product, protect carboxyl.Simple to operate, productivity is high, and solvent is recyclable.

5. trans-the N-of DL is anti-through deprotection to Methyl benzenesulfonyl base-octahydro-1H-indole-2-ethyl formate Should obtain the trans-octahydro-1H-indole-2-ethyl formate of DL, then hydrolysis obtains the trans-octahydro of DL -1H-indole-2-carboxylic acid, simple to operate, purity is high, solvent recoverable, and is separating the process of product In without using strong-acid ion exchange resin, it is adaptable to synthesize on a large scale, and easy to operate.

6. trans-octahydro-1H-the indole-2-carboxylic acid of DL and phenmethylol obtain the trans-octahydro-1H-indoles of DL -2-benzyl formate, simple to operate, purity is high.The recyclable recycling of solvent.

7. trans-octahydro-1H-indole-2-carboxylic acid the benzyl ester of DL uses cheap tartaric acids resolving agent, can obtain To optically pure (2S, 3aR, 7aS)-octahydro-1H-indole-2-carboxylic acid benzyl ester, low cost, solvent reusable edible.

Compared with prior art, trandolapril intermediate of the present invention (2S, 3aR, 7aS)-octahydro-1H-indoles-2-first The preparation method route of acid benzyl ester is short, preparation method rational technology, the reagent safety of employing, with low cost, no Polluting environment, having the advantages such as simple to operate, separation is easy simultaneously, the product yield preparing is high, optics Purity is high.The present invention, while substantially increasing the combined coefficient of Trandolapril, reduce further cost, Reduce the poisonous use having and polluting reagent, it is adaptable to synthesize on a large scale.

Detailed description of the invention

Below in conjunction with specific embodiment, the present invention is described in detail.Following example will assist in this area Technical staff is further appreciated by the present invention, but does not limit the present invention in any form.It should be pointed out that, to this For the those of ordinary skill in field, without departing from the inventive concept of the premise, some deformation can also be made And improvement.These broadly fall into protection scope of the present invention.

Embodiment 1

(1) synthesis of hexamethylene ethylene imine (hereinafter referred to as compound 2)

Chloramine-T (500g, 1.775mol), cyclohexene (164.0g, 2.0mol), iodine (28.2g, 0.11mol) Add the mixed of 1000mL oxolane and 500mL water with benzyltrimethylammonium bromide (20.4g, 0.088mol) In bonding solvent, room temperature reaction 24h, boil off oxolane, aqueous phase is extracted by ethyl acetate (500mL × 3), Merging organic phase, being dried with anhydrous sodium sulfate, suction filtration, rotation is evaporated off solvent, by product ethyl alcohol recrystallization, White crystal (326.7g, 65%) can be obtained.

(2) trans-N-of DL is to Methyl benzenesulfonyl base-2-(2-acrylic)-cyclohexylamine (hereinafter referred to as compound 3) Synthesis

Hexamethylene ethylene imine (25.1g, 0.1mol) and copper bromide (2.23g, 0.01mol) are dissolved in 200mL second It in ether, by allylic bromination magnesium (29.0g, 0.2mol) at-40 DEG C, is slowly added dropwise, is stirred overnight.Use water Cancellation is reacted, and with ethyl acetate (250mL × 3) extraction, merges organic phase, is dried with anhydrous sodium sulfate, suction filtration, Rotation is evaporated off solvent, obtains white solid (7.8g, 95%).

(3) synthesis of the trans-octahydro-1H-indoles-2-methyl alcohol (hereinafter referred to as compound 4) of DL

Trans-N-is dissolved in 200 to Methyl benzenesulfonyl base-2-(2-acrylic)-cyclohexylamine (29.3g, 0.1mol) Peracetic acid (7.6g, 0.1mol) is dissolved in 30mL dichloromethane by mL dichloromethane, at 0 DEG C～5 DEG C bars It is slowly added dropwise under part, adds and be stirred overnight, add potassium carbonate stirring 3h, filter, add 300mL water, With dichloromethane (150mL × 3) extraction, merging organic phase, being dried with anhydrous sodium sulfate, suction filtration, rotation is evaporated off Solvent, obtains grease (25.1g, 85%).

(4) trans-N-of DL is to Methyl benzenesulfonyl base-octahydro-1H-indole-2-carboxylic acid (hereinafter referred to as compound 5) synthesis

Compound 4 (29.5g, 0.1mol) is dissolved in 200mL dichloromethane, under conditions of-20 DEG C to room temperature, It is slowly added dropwise the aqueous solution (60mL) of potassium permanganate, room temperature reaction 8h after dropping, use dichloromethane (200 afterwards ML × 3) extraction, merge organic phase, be dried with anhydrous sodium sulfate, suction filtration, rotation steams solvent, obtains yellowish Look solid 22g, recrystallizes to obtain white solid (18.1g, 56%).

(5) Methyl benzenesulfonyl base-octahydro-1H-indole-2-ethyl formate (is hereinafter referred to as changed by the trans-N-of DL Compound 6) synthesis

Compound 5 (32.3g, 0.1mol) is dissolved in 650mL methyl alcohol, adds the 10mL concentrated sulfuric acid, and reflux 5h, After TLC monitoring reaction completely, after the washing of 200mL water, dichloromethane (300mL × 3) extracts, suction filtration, It is spin-dried for solvent, obtain pale yellow oil (32.1g, 95%).

(6) synthesis of the trans-octahydro-1H-indole-2-ethyl formate (hereinafter referred to as compound 7) of DL

Compound 6 (33.7g, 0.1mol) is dissolved in methyl alcohol, adds excessive Mg powder (48.0g, 2.0mol.) stirred At night, after TLC monitoring reaction completely, solvent methanol is spin-dried for, constantly uses dichloromethane washing system, and will Its load is on a silica gel column.Collect the solution that is filtrated to get, be spin-dried for solvent, obtain pale yellow oil (17.0g, 93%)。

(7) synthesis of the trans-octahydro-1H-indole-2-carboxylic acid (hereinafter referred to as compound 8) of DL

7 (1.8g, 0.01mol) are dissolved in methyl alcohol (20mL), add NaOH solution (0.8g, 15mL) to system, It is stirred overnight at room temperature, after TLC determines raw material reaction completely, after system internal solvent is spin-dried for, extract with dichloromethane (30mL × 3), anhydrous sodium sulfate is dried rear suction filtration.Rotation is evaporated off solvent, obtains white solid (1.6g, 92%).

(8) synthesis of the trans-octahydro-1H-indole-2-carboxylic acid benzyl ester (hereinafter referred to as compound 9) of DL

Compound 8 (25.0g, 0.15mol) and phenmethylol (25g, 0.23mol) are dissolved in 200mL toluene, add Enter p-methyl benzenesulfonic acid (1.7g, 10mmol), reflux dewatering, 2h is stirred at room temperature after reaction 8h static, adds Ether cooling stands.White solid is had to separate out.Suction filtration, obtains white solid 40.1g, by this solid, and freezing weight Crystallization, filters to obtain white solid 18.1g.Above-mentioned solid is dissolved in 100mL dichloromethane, at ice bath bar Under part, being slowly added dropwise saturated sodium bicarbonate saturated solution to pH is 10, stirs 0.5h, extracts with dichloromethane Take, merge organic phase, be dried with anhydrous sodium sulfate, rotation solvent is evaporated off, obtain pale yellow oil (10.1g, 39%)。

(9) recrystallization of octahydro-1H-indole-2-carboxylic acid benzyl ester (hereinafter referred to as compound 10)

It is dissolved in DL compound 9 (20.0g, 0.08mol) in ethanol (100mL), be slowly stirred under room temperature 0.5h, stands, 10 DEG C of placements, separates out a pair raceme white crystal (8.1g, 80%).

(10) fractionation of (2S, 3aR, 7aS)-octahydro-1H-indole-2-carboxylic acid benzyl ester (hereinafter referred to as compound 11)

Compound 10 (16.0g, 0.06mol) recrystallization crystal is dissolved in the mixed solvent 90mL of DMF/ acetonitrile, It is slowly added to L-acetyltartaric acid (23.0g, 0.1mol) under room temperature condition, stirs 0.5h, stand, separate out solid Body, filters to obtain white 21g.Solid is dissolved in the mixed liquor 150mL of dichloromethane and water, under condition of ice bath, It is slowly added dropwise the saturated solution of sodium acid carbonate, stir 0.5h.With dichloromethane extraction, merge organic phase, use Anhydrous sodium sulfate is dried, suction filtration, and rotation is evaporated off solvent, is dissolved in methyl alcohol, acidifying, and pH to 1-2 separates out white Solid (8.5g).

Embodiment 2

Toluene-sodium-sulfonchloramide (500.0g, 1.775mol), cyclohexene (164g, 2.0mol), iodine (28.2g, 0.11mol) Add 1000mL oxolane and 500mL water with benzyltrimethylammonium chloride (16.5g, 0.088mol) In mixed solvent, room temperature reaction 24h.Boiling off oxolane, aqueous phase is extracted by ethyl acetate (500mL × 3), Merging organic phase, being dried with anhydrous sodium sulfate, suction filtration, rotation is evaporated off solvent, by product ethyl alcohol recrystallization, White crystal (270.1g, 60%) can be obtained.

Hexamethylene ethylene imine (25.1g, 0.1mol) and copper bromide (2.23g, 0.01mol) are dissolved in 200mL second It in ether, by allylic bromination magnesium (58g, 0.4mol) at-50 DEG C, is slowly added dropwise, is stirred overnight.Use water Cancellation is reacted, and with ethyl acetate (250mL × 3) extraction, merges organic phase, is dried with anhydrous sodium sulfate, takes out Filter, rotation is evaporated off solvent, obtains white solid (29.1g, 99%).

Trans-N-is dissolved in 200 to Methyl benzenesulfonyl base-2-(2-acrylic)-cyclohexylamine (29.3g, 0.1mol) Metachloroperbenzoic acid (35.0g, 0.2mol) is dissolved in 100mL water ,-10 DEG C of conditions by mL dichloromethane Under be slowly added dropwise, add and be stirred overnight, add potassium carbonate stirring 3h, filter, add 300mL water, use Dichloromethane (150mL × 3) extracts, and merges organic phase, is dried with anhydrous sodium sulfate, suction filtration, and rotation is evaporated off Solvent, obtains grease (22.2g, 74%).

Compound 4 (29.5g, 0.1mol) is dissolved in 200mL dichloromethane, under conditions of 0 DEG C to room temperature, It is slowly added dropwise chromium trioxide (15.0g, 0.15mol) and the concentrated sulfuric acid (8.2mL) aqueous solution (60mL), after dropping Room temperature reaction 8h, afterwards with dichloromethane (200mL × 3) extraction, merges organic phase, is dried with anhydrous sodium sulfate, Suction filtration, rotation steams solvent, obtains faint yellow solid 22g.Recrystallize to obtain white solid (16.2g, 50%). (5) trans-N-of DL is to Methyl benzenesulfonyl base-octahydro-1H-indole-2-ethyl formate (hereinafter referred to as chemical combination Thing 6) synthesis

Compound 5 (32.4g, 0.1mol) is dissolved in 300mL methyl alcohol, adds the thionyl chloride of catalytic amount, backflow Overnight, rotation is evaporated off solvent and obtains pale yellow oil (33.1g, 98%)

At-78 DEG C, with oxolane as solvent, the crude product (33.7g, 0.1mol) to 5 adds 10 The sodium naphthalene of equivalent brand-new, removes ice bath when solution becomes white recession from navy blue, is warmed to room temperature slowly, is stirred overnight, After TLC determines raw material reaction completely, add saturated ammonium chloride cancellation reaction.Rotation is evaporated off solvent, uses strong acid Property amberlite Ester exchange separate, with 5% ammoniacal liquor elute, obtain pale yellow oil (18.1g, 99%).

Compound 7 (18.3g, 0.1mol) adds potassium hydroxide (11.2g, 0.2mol), with 300mL methyl alcohol-100 ML water makees solvent.After being stirred overnight, after TLC determines raw material reaction completely, solvent is removed in rotation, extracts with dichloromethane Take (300mL × 3), anhydrous magnesium sulfate is dried, suction filtration, be spin-dried for solvent and obtain white solid 6 (16.8g, 99%) (8) synthesis of the trans-octahydro-1H-indole-2-carboxylic acid benzyl ester (hereinafter referred to as compound 9) of DL

Compound 8 (25.0g, 0.15mol) and phenmethylol (25.0g, 0.23mol) are dissolved in 200mL toluene, Add the toluenesulfonic acid (1.7g, 10mmol) to catalytic amount, reflux dewatering, after reaction 8h, 2h is stirred at room temperature Static, add ether cooling to stand.White solid is had to separate out.Suction filtration, obtains white solid 40.1g, and this is solid Body, frozen recrystallization, filters to obtain white solid 18.1g.Above-mentioned solid is dissolved in 100mL dichloromethane, Under condition of ice bath, being slowly added dropwise saturated sodium bicarbonate saturated solution to pH is 10, stirs 0.5h, with two Chloromethanes extracts, and merges organic phase, is dried with anhydrous sodium sulfate, and rotation is evaporated off solvent, obtains faint yellow oily Thing (10.1g, 39%).

(10) fractionation of (2S, 3aR, 7aS)-octahydro indole-2-carboxylic acid benzyl ester (hereinafter referred to as compound 11)

Compound 10 (16g, 0.06mol) recrystallization crystal is dissolved in the mixed solvent 90mL of DMF/ acetonitrile, It is slowly added to L-acetyltartaric acid (23g, 0.1mol) under room temperature condition, stirs 0.5h, stand, separate out solid, Filter to obtain white 21.0g.Solid is dissolved in the mixed liquor 150mL of dichloromethane and water, under condition of ice bath, It is slowly added dropwise the saturated solution of sodium acid carbonate, stir 0.5h.With dichloromethane extraction, merge organic phase, use Anhydrous sodium sulfate is dried, suction filtration, and rotation is evaporated off solvent, is dissolved in methyl alcohol, acidifying, and pH to 1-2 separates out white Solid (8.5g).

Embodiment 3

Toluene-sodium-sulfonchloramide (500.0g, 1.775mol), cyclohexene (164.0g, 2.0mol), iodine (28.2g, 0.11mol) And benzyltrimethylammonium chloride (16.5g, 0.088mol) adds the mixing of 1000mL acetonitrile and 500mL water In solvent, room temperature reaction 24h.Boiling off acetonitrile, aqueous phase is extracted by ethyl acetate (500mL × 3), is associated with Machine phase, is dried by anhydrous sodium sulfate, suction filtration, and rotation is evaporated off solvent, by product ethyl alcohol recrystallization, can obtain in vain Look crystal (275g, 61%).

Hexamethylene ethylene imine (25.1g, 0.1mol) and copper bromide (2.23g, 0.01mol) are dissolved in 200mL tetra- It in hydrogen furans, by allylic bromination magnesium (58.0g, 0.4mol) at-50 DEG C, is slowly added dropwise, is stirred overnight. Go out reaction with shrend, with ethyl acetate (250mL × 3) extraction, merge organic phase, be dried with anhydrous sodium sulfate, Suction filtration, rotation is evaporated off solvent, obtains white solid (29.0g, 99%).

Trans-N-is dissolved in 200 to Methyl benzenesulfonyl base-2-(2-acrylic)-cyclohexylamine (29.3g, 0.1mol) Trifluoro Peracetic acid (26.0g, 0.2mol) is dissolved in 100mL water, under the conditions of-5 DEG C by mL dichloromethane It is slowly added dropwise, add and be stirred overnight.Add potassium carbonate stirring 3h, filter, add 300mL water, with two Chloromethanes (150mL × 3) extracts, and merges organic phase, is dried with anhydrous sodium sulfate, suction filtration, and rotation is evaporated off molten Agent, obtains grease (23.8g, 80%).

Compound 4 (29.5g, 0.1mol) is dissolved in 200mL dichloromethane, under conditions of 0 DEG C to room temperature, It is slowly added dropwise red fuming nitric acid (RFNA) 50mL, room temperature reaction 8h after dropping.Afterwards with dichloromethane (200mL × 3) extraction, Merging organic phase, being dried with anhydrous sodium sulfate, suction filtration, rotation steams removing solvent, obtains faint yellow solid 22g, Recrystallize to obtain white solid (14.0g, 46%).

Compound 5 (32.3g, 0.1mol) is dissolved in the methyl alcohol of 500mL, backflow 10 under the catalysis of concentrated hydrochloric acid After h, TLC determine raw material reaction completely, after the washing of 200mL water, dichloromethane (300mL × 3) extracts, Suction filtration, is spin-dried for solvent, obtains yellow oil (33.4g, 99%)

(6) synthesis of the trans octahydro-1H-indole-2-ethyl formate (hereinafter referred to as compound 7) of DL

At-78 DEG C, with oxolane as solvent, the crude product (33.7g, 0.1mol) to 5 adds 15g It in the lithium naphthalene of the brand-new of individual equivalent, is slowly increased to room temperature, is stirred overnight, after TLC determines raw material reaction completely, Add saturated ammonium chloride cancellation reaction.Rotation is evaporated off solvent, separates with strong-acid ion exchange resin exchange, uses 5% ammoniacal liquor wash-out, obtains pale yellow oil 10 (16.5g, 90%)

At room temperature, in the methanol solution of 7 (18.3g, 0.1mol), lithium hydroxide (8.4g, 0.2mol.) is added The aqueous solution, be stirred overnight, after TLC determines raw material reaction completely, take out after dichloromethane (300mL × 3) extraction Filter, be spin-dried for, obtain white solid (16.8g, 99%)

Compound 8 (30.0g, 0.18mol) and phenmethylol (30g, 0.28mol) are dissolved in 200mL toluene, add P-methyl benzenesulfonic acid (2.0g, 11.6mmol), reflux dewatering, it is warmed to room temperature after reaction 10h, be slowly added dropwise saturated Saturated solution of sodium bicarbonate is 10.0 to pH, stirs 2h, with dichloromethane extraction, merges organic phase, uses Anhydrous sodium sulfate is dried, and rotation is evaporated off solvent, obtains pale yellow oil (44.6g, 97%).

Compound 9 (20.0g, 0.12mol) is dissolved in isopropanol (100mL), is slowly stirred 0.5h under room temperature, Stand, 5 DEG C of placements, separate out white crystal (8.8g, 88%).

Compound 10 (32.0g, 0.12mol) recrystallization crystal is dissolved in the mixed solvent 180mL of DMF/ ether, It is slowly added to L-acetyltartaric acid (46.0g, 0.2mol) under room temperature condition, stirs 0.5h, stand, separate out solid, Filter to obtain white 42.1g, solid is dissolved in the mixed liquor 150mL of dichloromethane and water, under condition of ice bath, It is slowly added dropwise the saturated solution of sodium acid carbonate, stirs 0.5h, with dichloromethane extraction, merge organic phase, use Anhydrous sodium sulfate is dried, suction filtration, and rotation is evaporated off solvent, is dissolved in methyl alcohol, acidifying, pH to 1-2, separate out white Look solid (7.5g).

Embodiment 4

Chloramine-T (500g, 1.775mol), cyclohexene (164g, 2.0mol), iodine (28.2g, 0.11mol) and In the mixed solvent of TBAB (28.0g, 0.088mol) addition 1000mL acetonitrile and 500mL water, Room temperature reaction 24h, boils off acetonitrile, and aqueous phase is extracted by ethyl acetate (500mL × 3), merges organic phase, uses Anhydrous sodium sulfate is dried, suction filtration, and rotation is evaporated off solvent, by product ethyl alcohol recrystallization, can obtain white crystal (248.2 g,55%)。

Hexamethylene ethylene imine (25.1g, 0.1mol) and cupric iodide (1.9g, 0.01mol) are dissolved in 200mL tetra- It in hydrogen furans, by allylic bromination magnesium (58.0g, 0.4mol) at-50 DEG C, is slowly added dropwise, is stirred overnight. Go out reaction with shrend, with ethyl acetate (250mL × 3) extraction, merge organic phase, be dried with anhydrous sodium sulfate, Suction filtration, rotation is evaporated off solvent, obtains white solid (25.4g, 85%).

Trans-N-is dissolved in 200 to methyl this sulfonyl-2-(2-acrylic)-cyclohexylamine (29.3g, 0.1mol) Benzoyl hydroperoxide (27.6g, 0.2mol) is dissolved in 100mL dichloromethane, at-10 DEG C of bars by mL dichloromethane It is slowly added dropwise under part, adds and be stirred overnight, add potassium carbonate stirring 3h, filter, add 300mL water, With dichloromethane (150mL × 3) extraction, merging organic phase, being dried with anhydrous sodium sulfate, suction filtration, rotation is evaporated off Remove solvent, obtain grease (24.2g, 81%).

Compound 4 (29.5g, 95mmol) is dissolved in 200mL dichloromethane, under conditions of 0 DEG C to room temperature, By NaClO₂(20g, 0.19mol), NaOCl (7.06,95mmol) is separately added into room temperature reaction 8h after dropping, Afterwards with dichloromethane (200mL × 3) extraction, merging organic phase, being dried with anhydrous sodium sulfate, suction filtration, rotation is steamed Go out solvent, obtain faint yellow solid 22.2g, recrystallize to obtain white solid (30.4g, 99%).

(5) trans-N-of DL is to Methyl benzenesulfonyl base-octahydro-1H-indole-2-ethyl formate (hereinafter referred to as chemical combination Thing 6) synthesis

Compound 5 (32.3g, 0.1mol) is dissolved in 500mL methyl alcohol, adds 2,2-dimethoxy third in system Alkane (20.8g, 0.2mol), under the hydrochloric acid of catalytic amount, room temperature reaction is overnight, after TLC monitoring reaction completely, uses After the washing of 200mL water, dichloromethane (300mL × 3) extracts, and suction filtration is spin-dried for solvent, obtains yellow oily Thing (28.3g, 84%)

At-78 DEG C, with oxolane as solvent, the crude product (33.7g, 0.1mol) to 5 adds 20 The lithium naphthalene of the brand-new of equivalent, is slowly increased to room temperature, is stirred overnight, and adds saturated ammonium chloride cancellation reaction.Rotation is steamed Remove solvent, separate with strong-acid ion exchange resin exchange, with 5% ammoniacal liquor wash-out, obtain faint yellow oily Thing (18.0g, 98%).

At room temperature, in the isopropanol-water solutions of 7 (18.3g, 0.1mol), NaOH (8.0g, 0.2mol) is added, It is stirred overnight after TLC determines raw material reaction completely, with suction filtration after dichloromethane (300mL × 3) extraction, be spin-dried for, Obtain white solid 6 (16.8g, 99%)

Compound 8 (30.0g, 0.18mol) and phenmethylol (30.0g, 0.28mol) are dissolved in 200mL toluene, add Enter benzene sulfonic acid (2.0g, 11.6mmol), reflux dewatering, be warmed to room temperature after reaction 10h, be slowly added dropwise saturated carbon Acid hydrogen sodium saturated solution is 10 to pH, stirs 2h, with dichloromethane extraction, merges organic phase, with anhydrous Sodium sulphate is dried, and rotation is evaporated off solvent, obtains pale yellow oil (44.6g, 97%).

(9) recrystallization of the trans-octahydro-1H-indole-2-carboxylic acid benzyl ester (hereinafter referred to as compound 10) of DL

Compound 9 (20.0g, 0.08mol) is dissolved in petrol ether/ethyl acetate (100mL), slowly stirs under room temperature Mix 0.5h, stand, 0 DEG C of placement, separate out white crystal (8.6g, 86%).

Octahydro indole-2-carboxylic acid benzyl ester (1.0g, 3.86mmol) of racemization is dissolved in normal heptane: ethyl acetate The mixed solvent 200mL of=30:70, is prepared with suitably preparing post under conditions of 30 degree.Available light Learn pure (2S, 3aR, 7aS)-octahydro-1H-indole-2-carboxylic acid benzyl ester (0.46g, 92%).

Embodiment 5

Toluene-sodium-sulfonchloramide (500.0g, 1.775mol), cyclohexene (164.0g, 2.0mol), iodine (28.2g) and benzyl three In the mixed solvent of ammonio methacrylate (16.5g, 0.088mol) addition 1000mL acetonitrile and 500mL water, Room temperature reaction 24h.Boiling off acetonitrile, aqueous phase is extracted by ethyl acetate (500mL × 3), merges organic phase, uses Anhydrous sodium sulfate is dried, suction filtration, and rotation is evaporated off solvent, by product ethyl alcohol recrystallization, can obtain white crystal (275.0g,61%)。

Hexamethylene ethylene imine (25.1g, 0.1mol) and copper bromide (2.23g, 0.01mol) are dissolved in 200mL tetra- It in hydrogen furans, by allylic bromination magnesium (58.0g, 0.4mol) at-50 DEG C, is slowly added dropwise, is stirred overnight. Go out reaction with shrend, with ethyl acetate (250mL × 3) extraction, merge organic phase, be dried with anhydrous sodium sulfate, Suction filtration, rotation is evaporated off solvent, obtains white solid (29g, 99%).

Trans-N-is dissolved in 200 to Methyl benzenesulfonyl base-2-(2-acrylic)-cyclohexylamine (29.3g, 0.1mol) Trifluoro Peracetic acid (26g, 0.2mol) is dissolved in 100mL water by mL dichloromethane, slow under the conditions of-5 DEG C Slow dropping, adds and is stirred overnight, and adds potassium carbonate stirring 3h.Filter, add 300mL water, use dichloro Methane (150mL × 3) extracts, and merges organic phase, is dried with anhydrous sodium sulfate, suction filtration, and rotation is evaporated off solvent, Obtain grease (23.8g, 80%).

Compound 4 (29.5g) is dissolved in 200mL dichloromethane, under conditions of 0 DEG C to room temperature, is slowly added dropwise Red fuming nitric acid (RFNA) 50mL, room temperature reaction 8h after dropping, afterwards with dichloromethane (200mL × 3) extraction, merge organic Phase, is dried by anhydrous sodium sulfate, suction filtration, and rotation steams solvent, obtains faint yellow solid 22g, recrystallizes White solid (14g, 46%).

Compound 5 (32.3g, 0.1mol) is dissolved in the methyl alcohol of 500mL, backflow 0.5 under the catalysis of fluoboric acid After h, TLC monitoring reaction completely, wash with 200mL water after being spin-dried for solvent, with dichloromethane (300mL × 3) Extraction, magnesium sulfate is dried, be spin-dried for solvent after suction filtration obtains yellow oil (33.4g, 99%)

At-78 DEG C, with oxolane as solvent, the crude product (33.7g, 0.1mol) to 6 adds 15 The sodium naphthalene of equivalent brand-new, is slowly increased to room temperature, is stirred overnight, and after TLC determines raw material reaction completely, adds Saturated ammonium chloride cancellation is reacted.Rotation is evaporated off solvent, separates with strong-acid ion exchange resin exchange, with 5% Ammoniacal liquor elutes, and obtains pale yellow oil (18.0g, 98%).

At room temperature, in the ethanol-water solution of 7 (18.3g, 0.1mol) add NaOH (8.02g, 0.2 Mol), it is stirred overnight, after TLC determines raw material reaction completely, take out after dichloromethane (300mL × 3) extraction Filter, be spin-dried for, obtain white solid (16.8g, 99%)

Compound 8 (30g) and phenmethylol (15g) are dissolved in 200mL dimethylbenzene, add benzene sulfonic acid (2g, 11.6 Mmol), reflux dewatering, is warmed to room temperature after reaction 10h, is slowly added dropwise saturated sodium bicarbonate saturated solution to pH Being 10.0, stirring 2h, with dichloromethane extraction, merge organic phase, be dried with anhydrous sodium sulfate, rotation is evaporated off Remove solvent, obtain pale yellow oil (44.6g, 97%).

Compound 7 (20.0g, 0.08mol) is dissolved in isopropanol 100mL, is slowly stirred 0.5h under room temperature, quiet Put, 5 DEG C of placements, separate out white crystal (8.8g, 88%).

Compound 10 (32.0g) recrystallization crystal is dissolved in the mixed solvent 180mL of DMF/ ether, room temperature bar It is slowly added to L-acetyltartaric acid (46.0g, 0.2mol) under part, stirs 0.5h, stand, separate out solid, mistake Filter to obtain white 42g, solid is dissolved in the mixed liquor 150mL of dichloromethane and water, under condition of ice bath, slowly The saturated solution of dropping sodium acid carbonate, stirs 0.5h, with dichloromethane extraction, merges organic phase, with anhydrous Sodium sulphate is dried, suction filtration, and rotation is evaporated off solvent, is dissolved in methyl alcohol, acidifying, and pH to 1-2 separates out white solid (7.6g)。

Embodiment 6

Toluene-sodium-sulfonchloramide (500.0g, 1.775mol), cyclohexene (164g, 2.0mol), iodine (28.2g, 0.11mol) Add 1000mL dichloromethane and 500mL water with benzyltriethylammoinium chloride (19.9g, 0.088mol) In mixed solvent, room temperature reaction 24h, boil off acetonitrile, aqueous phase is extracted by ethyl acetate (500mL × 3), closes And organic phase, it is dried with anhydrous sodium sulfate, suction filtration, rotation is evaporated off solvent, by product ethyl alcohol recrystallization, can Obtain white crystal (251.0g, 57%).

Cuprous to hexamethylene ethylene imine (25.1g, 0.1mol) and TFMS (2.12g, 0.01mol) is dissolved in It in 200mL oxolane, by allylic bromination magnesium (58g, 0.4mol) at-50 DEG C, is slowly added dropwise, stirs Mix overnight.Go out reaction with shrend, with ethyl acetate (250mL × 3) extraction, merge organic phase, use anhydrous sulphur Acid sodium is dried, suction filtration, and rotation is evaporated off solvent, obtains white solid (22.2g, 75%).

Compound 4 (29.5g, 0.1mol) is dissolved in the mixed solvent of 200mL dichloromethane and 100mL water, Under conditions of 0 DEG C to room temperature, by TEMPO (1.04g, 6.6mmol), NaOCl (7.06,95mmol) Be separately added into room temperature reaction 8h after dropping, after with dichloromethane extraction, merge organic phase, use anhydrous sodium sulfate Being dried, suction filtration, rotation steams solvent, obtains white solid (30.4g, 99%).

Compound 5 (32.3g, 0.1mol) is dissolved in the methyl alcohol of 500mL, and reflux under the catalysis of concentrated hydrochloric acid 2h, After TLC monitoring reaction completely, wash with 200mL water water after being spin-dried for solvent, with dichloromethane (300mL × 3) Extraction, magnesium sulfate is dried, obtain yellow oil (28.3g, 84%) with being spin-dried for solvent after suction filtration

At-78 DEG C, with oxolane as solvent, the crude product (33.7g, 0.1mol) to 5 adds 20 The sodium naphthalene of the brand-new of equivalent, is slowly increased to room temperature, is stirred overnight, and after TLC determines raw material reaction completely, adds Enter saturated ammonium chloride cancellation reaction.Rotation is evaporated off solvent, and spent ion exchange resin exchange separates, and uses 5% ammoniacal liquor Wash-out, obtains pale yellow oil (18.1g, 99%).

At room temperature, in the methanol-water solution of 7 (18.3g, 0.1mol) add NaOH (8.02g, 0.2 Mol), be stirred overnight, after TLC determines raw material reaction completely, with suction filtration after dichloromethane (300mL × 3) extraction, It is spin-dried for, obtain white solid (16.8g, 99%)

Compound 8 (30g, 0.18mol) and phenmethylol (30g, 0.28mol) are dissolved in 200mL toluene, add P-methyl benzenesulfonic acid (2g), reflux dewatering, 2h is stirred at room temperature after reaction 8h static, adds ether cooling to stand. White solid is had to separate out.Suction filtration, obtains white solid 45g, by this solid, frozen recrystallization, filters white Solid 20g.Above-mentioned solid is dissolved in 100mL dichloromethane, under condition of ice bath, is slowly added dropwise saturated Saturated solution of sodium bicarbonate is 10 to PH, stirs 0.5h, with dichloromethane extraction, merges organic phase, uses Anhydrous sodium sulfate is dried, and rotation is evaporated off solvent, obtains pale yellow oil (12g, 40%).

Compound 9 (20g, 0.08mol) is dissolved in isopropyl ether (100mL), is slowly stirred 0.5h under room temperature, quiet Put, 0 DEG C of placement, separate out white crystal (8.4g, 84%).

Recrystallization crystal by compound 10 (32.0g, 0.12mol) is dissolved in the mixed solvent 180 of DMF/ ether ML, is slowly added to L-to toluyl acyl tartaric acid (48g, 0.2mol), stirs 0.5h under room temperature condition, quiet Put, separate out solid, filter to obtain white 45.2g, solid is dissolved in the mixed liquor 150mL of dichloromethane and water, It under condition of ice bath, is slowly added dropwise the saturated solution of sodium acid carbonate, stirs 0.5h, with dichloromethane extraction, close And organic phase, it is dried with anhydrous sodium sulfate, suction filtration, rotation is evaporated off solvent, is dissolved in methyl alcohol, and acidifying, PH arrives 1-2, separates out white solid (7.4g).

Embodiment 7

Toluene-sodium-sulfonchloramide (500.0g, 1.775mol), cyclohexene (164.0g, 2.0mol), iodine (28.2g) and benzyl three In the mixed solvent of ammonio methacrylate (16.5g, 0.088mol) addition 1000mL acetonitrile and 500mL water, room Temperature reaction 24h, boils off acetonitrile, aqueous phase ethyl acetate 500mL × 3) extraction, merge organic phase, with anhydrous Sodium sulphate is dried, suction filtration, rotation solvent is evaporated off, by product ethyl alcohol recrystallization, can obtain white crystal (251g, 57%)。

Hexamethylene ethylene imine (25.1g, 0.1mol) and cuprous bromide dimethyl sulphide (2.1g, 0.01mol) are dissolved in It in 200mL oxolane, by allylic bromination magnesium (58g, 0.4mol) at-50 DEG C, is slowly added dropwise, stirs Mix overnight.Go out reaction with shrend, with ethyl acetate (250mL × 3) extraction, merge organic phase, use anhydrous slufuric acid Sodium is dried, suction filtration, and rotation is evaporated off solvent, obtains white solid (25g, 85%).

Trans-N-is dissolved in 200 to methyl this sulfonyl-2-(2-acrylic)-cyclohexylamine (29.3g, 0.1mol) Benzoyl hydroperoxide (27.6g, 0.2mol) is dissolved in 100mL dichloromethane, at-10 DEG C of bars by mL dichloromethane It is slowly added dropwise under part, add and be stirred overnight.Add potassium carbonate stirring 3h, filter, add 300mL water, With dichloromethane (150mL × 3) extraction, merging organic phase, being dried with anhydrous sodium sulfate, suction filtration, rotation is evaporated off Remove solvent, obtain grease (24.2g, 81%).

Compound 4 (29.5g, 0.1mol) is dissolved in 200mL dichloromethane, under conditions of 0 DEG C to room temperature, It is slowly added dropwise chromium trioxide (15.0g, 0.15mol) and the concentrated sulfuric acid (8.2mL) aqueous solution (60mL), after dropping Room temperature reaction 8h, afterwards with dichloromethane (200mL × 3) extraction, merges organic phase, is dried with anhydrous sodium sulfate, Suction filtration, rotation steams solvent, obtains faint yellow solid 22g, recrystallize to obtain white solid (16g, 50%).

Compound 5 (32.3g, 0.1mol) is dissolved in the methyl alcohol of 20 equivalents, backflow 2 under the catalysis of perchloric acid It is spin-dried for solvent, with the washing of 200mL water, with dichloromethane (300mL × 3) after h, TLC monitoring reaction completely Extraction, magnesium sulfate is dried, be spin-dried for solvent after suction filtration obtains yellow oil (29.7g, 88%)

At-78 DEG C, with oxolane as solvent, the crude product (33.7g, 0.1mol) to 6 adds 10 The lithium naphthalene of equivalent brand-new, is slowly increased to room temperature, is stirred overnight, and after TLC determines raw material reaction completely, adds Saturated ammonium chloride cancellation is reacted.Rotation is evaporated off solvent, separates with strong-acid ion exchange resin exchange, with 5 Ammoniacal liquor elutes, and obtains pale yellow oil (16.5g, 90%).

At room temperature, in the isopropanol-water solutions of 7 (18.3g, 0.1mol), add lithium hydroxide (5eq.), stir Mix overnight, after TLC determines raw material reaction completely, with suction filtration after dichloromethane (300mL × 3) extraction, be spin-dried for, To white solid (16.8g, 99%)

Compound 8 (30.0g, 0.18mol) and phenmethylol (30g, 0.28mol) are dissolved in 200mL toluene, add P-methyl benzenesulfonic acid (2g, 11.6mmol), reflux dewatering, 2h is stirred at room temperature after reaction 8h static, adds second Ether cooling stands.White solid is had to separate out.Suction filtration, obtains white solid 45g, by this solid, and frozen recrystallization, Filter to obtain white solid 20g.Above-mentioned solid is dissolved in 100mL dichloromethane, under condition of ice bath, slow Slow dropping saturated sodium bicarbonate saturated solution is 10 to PH, stirs 0.5h, with dichloromethane extraction, merges Organic phase, is dried by anhydrous sodium sulfate, and rotation is evaporated off solvent, obtains pale yellow oil (12g, 40%).

Compound 9 (20g, 0.08mol) is dissolved in petrol ether/ethyl acetate (100mL), is slowly stirred under room temperature 0.5h, stands, and 0 DEG C of placement, separates out white crystal (8.6g, 86%).

Recrystallization crystal by compound 10 (32.0g, 0.12mol) is dissolved in the mixed solvent 180 of DMF/ ether ML, is slowly added to L-benzoyl acyl tartaric acid (44.0g, 0.19mol) under room temperature condition, stir 0.5h, stands, Separate out solid, filter to obtain white 44.3g, solid is dissolved in the mixed liquor 150mL of dichloromethane and water, ice It under the conditions of bath, is slowly added dropwise the saturated solution of sodium acid carbonate, stirs 0.5h, with dichloromethane extraction, merge Organic phase, is dried by anhydrous sodium sulfate, suction filtration, and rotation is evaporated off solvent, is dissolved in methyl alcohol, acidifying, pH to 1-2, Separate out white solid (7.2g).

Embodiment 8

Chloramine-T (563.4g, 2.0mol), cyclohexene (82.2g, 1.0mol), NBS (356.0g, 2mol) and iodine (2.5g, 9.85mmol) adds in 5L acetonitrile solvent, after room temperature reaction 24h, TLC detection reaction terminates, Precipitation in diatomite drainage removing system, washes with water three times afterwards, and magnesium sulfate is dried, suction filtration, boils off molten Obtain white solid, recrystallizing methanol after agent, white crystal (238.8g, 95%) can be obtained.

Compound 1 (25.1g, 0.1mol) and cuprous iodide (1.9g, 0.01mol) are dissolved in 300mL ether In, it by allylic bromination magnesium (29.0g, 0.2mol) at-50 DEG C, is slowly added dropwise, is stirred overnight.Use shrend Go out reaction, with ethyl acetate (250mL × 3) extraction, merge organic phase, be dried with anhydrous magnesium sulfate, suction filtration, Rotation is evaporated off solvent, obtains white solid 2 (28.8g, 98%).

Trans-N-is dissolved in 200 to methyl this sulfonyl-2-(2-acrylic)-cyclohexylamine (29.3g, 0.1mol) Benzoyl hydroperoxide (27.6g, 0.2mol) is dissolved in 100mL dichloromethane, at-10 DEG C of bars by mL dichloromethane It is slowly added dropwise under part, add and be stirred overnight.Add sodium carbonate stirring 3h, filter, add 300mL water, With dichloromethane (150mL × 3) extraction, merging organic phase, being dried with anhydrous sodium sulfate, suction filtration, rotation is evaporated off Remove solvent, obtain grease (29.4g, 95%).

Compound 3 (30.9g, 0.1mol) is dissolved in 350mL15% sodium bicarbonate solution and 1200mL acetone, It under conditions of room temperature, is slowly added to 2,2,6,6-tetramethyl piperidine nitrogen oxides (0.78g, 5mmol) and trichlorine Isocyanuric acid (46.5g, 0.2mol), sodium bromide (1.71g, 16.67mmol) reaction 6h, TLC monitoring has been reacted Going out with shrend after Quan, organic layer is extracted three times by ether, with saturated aqueous common salt washing, is dried with anhydrous sodium sulfate, Suction filtration, rotation is evaporated off solvent, obtains faint yellow solid, recrystallize to obtain white solid 4 (32.0g, 99%).

Compound 5 (32.3g, 0.1mol) is dissolved in the oxolane of 500mL, adds equivalent in system Sodium hydrate aqueous solution, backward system in add 1.2 equivalents iodomethane, react overnight TLC monitoring Go out reaction with shrend after reaction completely, after dichloromethane extraction three times, sodium sulphate is dried, suction filtration, be spin-dried for molten Agent obtains yellow oil (33.4g, 99%)

At-78 DEG C, with oxolane as solvent, the crude product (33.7g, 0.1mol) to 6 adds 10 The lithium naphthalene of equivalent brand-new, is slowly increased to room temperature, is stirred overnight, and after TLC determines raw material reaction completely, adds Saturated ammonium chloride cancellation is reacted.Rotation is evaporated off solvent, separates with strong-acid ion exchange resin exchange, with 5% Ammoniacal liquor elutes, and obtains pale yellow oil (16.5g, 90%).

At room temperature, in the isopropanol-water solutions of 7 (36.6g, 0.1mol), add lithium hydroxide (5eq.), stir Mix overnight, after TLC determines raw material reaction completely, with suction filtration after dichloromethane (300mL × 3) extraction, be spin-dried for, To white solid (33.6g, 99%)

Compound 8 (30g, 0.18mol) and phenmethylol (30g, 0.28mol) are dissolved in 200mL benzene, add to first Benzene sulfonic acid (3.0g, 17.44mmol), reflux dewatering, 2h is stirred at room temperature after reaction 8h static, adds ether Cooling stands.White solid is had to separate out.Suction filtration, obtains white solid 45g, by this solid, and frozen recrystallization, Filter to obtain white solid 20g.Above-mentioned solid is dissolved in 100mL dichloromethane, under condition of ice bath, slow Slow dropping saturated sodium bicarbonate saturated solution is 10 to PH, stirs 0.5h, with dichloromethane extraction, merges Organic phase, is dried by anhydrous sodium sulfate, and rotation is evaporated off solvent, obtains pale yellow oil (12g, 40%).

Compound 9 (20g, 0.08mol) is dissolved in petrol ether/ethyl acetate (100mL), is slowly stirred under room temperature 0.5h, stands, and 5 DEG C of placements, separates out white crystal (8.6g, 86%).

Recrystallization crystal by compound 10 (32.0g, 0.12mol) is dissolved in the mixed solvent 180 of DMF/ ether ML, is slowly added to L-benzoyl acyl tartaric acid (44g, 0.19mol) under room temperature condition, stir 0.5h, stands, Separate out solid, filter to obtain white 44.1g, solid is dissolved in the mixed liquor 150mL of dichloromethane and water, ice It under the conditions of bath, is slowly added dropwise the saturated solution of sodium acid carbonate, stirs 0.5h, with dichloromethane extraction, merge Organic phase, is dried by anhydrous sodium sulfate, suction filtration, and rotation is evaporated off solvent, is dissolved in methyl alcohol, acidifying, pH to 1.5, Separate out white solid (7.2g).

Above the specific embodiment of the present invention is described.It is to be appreciated that the present invention not office Being limited to above-mentioned particular implementation, those skilled in the art can make various within the scope of the claims Deformation or modification, this has no effect on the flesh and blood of the present invention.

Claims

1. a preparation method for trandolapril intermediate, described trandolapril intermediate refer to (2S, 3aR, 7aS)- Octahydro-1H-indole-2-carboxylic acid benzyl ester, preparation method is:

In a solvent with oxidizing obtain trans DL N-to Methyl benzenesulfonyl base-octahydro-1H-indoles-2- Formic acid, described solvent be oxolane, ether, dichloromethane, chloroform, acetonitrile, toluene, methyl alcohol, ethanol, Any one in isopropanol, DMF, DMSO, acetone-water, carbon tetrachloride, its consumption is 100mL～5000 ML/ mole, reaction temperature is-30 DEG C～50 DEG C；

Oxidant used is ozone, hydrogen peroxide, Peracetic acid, benzoyl hydroperoxide, metachloroperbenzoic acid, height Potassium manganate, chromium trioxide/concentrated sulfuric acid, red fuming nitric acid (RFNA), sodium hypochlorite, sodium chlorite, sym-closene, three Any one in fluorine Peracetic acid, sodium metaperiodate；

The reaction of this stage oxidation uses or does not use catalyst, and when using catalyst, described catalyst is 2,2,6,6-tetramethyl piperidine-nitrogen-oxide, sodium bromide, KBr, sodium chloride, potassium chloride, sodium fluoride, fluorine Any one in change potassium, lithium fluoride, TBAB, hydrate ruthenium trichloride, iron chloride hexahydrate；

4th step, the N-of trans DL carries out esterification guarantor to Methyl benzenesulfonyl base-octahydro-1H-indole-2-carboxylic acid Protect carboxyl and obtain the N-of DL to Methyl benzenesulfonyl base-octahydro-1H-indole-2-ethyl formate；Esterification condition is Methyl alcohol/acidic catalyst, 2,2-dimethoxypropane/acidic catalyst, iodomethane/alkali, dimethyl suflfate/alkali, Diazomethane/acid, wherein methyl alcohol, 2,2-dimethoxypropane, iodomethane, dimethyl suflfate, diazomethane with The molar feed ratio of raw material is 1:1～100:1, and reaction temperature is 0 DEG C～100 DEG C；

Described acidic catalyst is sulfuric acid, hydrochloric acid, perchloric acid, p-methyl benzenesulfonic acid, benzene sulfonic acid, acetic acid, dichloro Any one in sulfoxide, fluoboric acid；

Described alkali is NaOH, potassium hydroxide, barium hydroxide, calcium hydroxide；Described acid includes hydrochloric acid, sulphur Acid, benzene sulfonic acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, any one in perchloric acid；

5th step, the N-of trans DL to Methyl benzenesulfonyl base-octahydro-1H-indole-2-ethyl formate through sloughing nitrogen Upper p-toluenesulfonyl obtains the octahydro-1H-indole-2-ethyl formate of trans DL；Reaction condition used is magnesium / methyl alcohol, sodium naphthalene/oxolane, lithium naphthalene/oxolane, reaction temperature is-80 DEG C～100 DEG C；

6th step, the octahydro-1H-indole-2-ethyl formate of trans DL obtains the octahydro of trans DL through hydrolysis -1H-indole-2-carboxylic acid；Hydrolysing agent used is hydrazine hydrate, ammoniacal liquor, NaOH, potassium hydroxide, hydrogen-oxygen Change any one of lithium, hydrochloric acid, the octahydro-1H-indole-2-ethyl formate of described hydrolysing agent and trans DL Molar ratio be 1:1～20:1；

Described methyl esters hydrolysising solvent is any one of methanol-water, isopropanol-water, n-butanol-water, reaction temperature Degree is 0 DEG C～100 DEG C；

2. the preparation method of a kind of trandolapril intermediate according to claim 1, it is characterised in that: the In one step, the mol ratio of described chloramine-T and cyclohexene is 1:1～1:10, and the catalyst of the two reaction includes I₂、 The mol ratio of N-bromo-succinimide, N-bromo acetamide and phase transfer catalyst, catalyst and chloramine-T For 1:20～1:50, the solvent of reaction is all polarity that can be used for this reaction and non-polar solven.

3. the preparation method of a kind of trandolapril intermediate according to claim 2, it is characterised in that: institute State phase transfer catalyst be tetrabutylammonium iodide, TBAB, tetrabutylammonium chloride, tetramethyl-ammonium iodide, 4 bromide, tetramethyl ammonium chloride, benzyltrimethylammonium bromide, benzyltrimethylammonium chloride, benzyl three Any one phase transfer catalysis (PTC) in ethyl ammonium chloride, tri-n-octyl methyl ammonium chloride, DTAC Agent.

4. the preparation method of a kind of trandolapril intermediate according to claim 1, it is characterised in that: In second step, in described hexamethylene ethylene imine and allylic bromination reactive magnesium, rubbing of allylic bromination azoviolet Your consumption is 5 times of hexamethylene ethylene imine, this reaction used catalyst be copper chloride, stannous chloride, copper bromide, Cuprous bromide, cupric iodide, cuprous iodide, trifluoromethayl sulfonic acid copper, TFMS are cuprous, cuprous bromide two Methyl sulfide any one mantoquita therein；Catalyst is 1:10～1:100 with the mol ratio of allylic bromination magnesium, reaction Carry out at-78 DEG C～50 DEG C.

5. the preparation method of a kind of trandolapril intermediate according to claim 1, it is characterised in that: In 3rd step, reaction temperature is-5 DEG C.

6. the preparation method of a kind of trandolapril intermediate according to claim 1, it is characterised in that: In 4th step, methyl alcohol, 2,2-dimethoxypropane, iodomethane, dimethyl suflfate, diazomethane and raw material Molar feed ratio is 20:1.

7. the preparation method of a kind of trandolapril intermediate according to claim 1, it is characterised in that: In 4th step, reaction temperature is reflux temperature.

8. the preparation method of a kind of trandolapril intermediate according to claim 1, it is characterised in that: In 5th step and the 6th step, reaction temperature is 25 DEG C.

9. the preparation method of a kind of trandolapril intermediate according to claim 1, it is characterised in that: In 7th step, becoming benzyl ester reagent to be benzylalcohol, solvent is methyl alcohol, methyl alcohol, water, isopropanol, n-butanol, tertiary fourth In alcohol, oxolane, ether, dichloromethane, acetonitrile, toluene, carbon tetrachloride, ethyl acetate any one Kind, reaction temperature is 0 DEG C～100 DEG C.

10. the preparation method of a kind of trandolapril intermediate according to claim 1, it is characterised in that: In 8th step, described recrystallization, use solvent to be ethanol, methyl alcohol, isopropanol, toluene, acetone, acetic acid second Ester, dichloromethane, chloroform, methyl tertiary butyl ether(MTBE), isopropyl ether, ether, petroleum ether, pentamethylene, thiacyclohexane, A kind of or several mixed solvent, recrystallization temperature-70 in cycloheptane, pentane, normal hexane and normal heptane DEG C～50 DEG C.