CN104370777A - Intermediates for synthesizing (2R,5R)-1,6-diphenylhexyl-2,5-diamine and salts thereof, preparation method and applications of the intermediates - Google Patents

Intermediates for synthesizing (2R,5R)-1,6-diphenylhexyl-2,5-diamine and salts thereof, preparation method and applications of the intermediates Download PDF

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CN104370777A
CN104370777A CN201310351906.3A CN201310351906A CN104370777A CN 104370777 A CN104370777 A CN 104370777A CN 201310351906 A CN201310351906 A CN 201310351906A CN 104370777 A CN104370777 A CN 104370777A
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formula
intermediate
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CN201310351906.3A
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李金亮
赵楠
罗光顺
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上海迪赛诺化学制药有限公司
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Abstract

The invention discloses intermediates for synthesizing (2R,5R)-1,6-diphenylhexyl-2,5-diamine and salts thereof, a preparation method and applications of the intermediates. The intermediates are compounds represented by the structural formula II and the structural formula III. (2R,5R)-1,6-diphenylhexyl-2,5-diamine and salts thereof, which are prepared from the provided intermediates, can reach a HPLC purity of 99% or more without any complicated post-treatment, and the total mole yield can reach 80% or more. Furthermore, the preparation method of the intermediates is simple, the reaction conditions are mild, the post treatment is simple and easy to operate, the raw materials are cheap and easily-available, the mole yield in each step can reach 80% or more, the purity of reaction products in each step can reach 90% or more, and the provided intermediates have a very important meaning and practical value for carry out low cost and massive production of high purity cobicistat.

Description

Synthesis (2R, 5R)-1,6-diphenyl hexane-2,5-diamines and the intermediate of salt thereof and the preparation method and application of described intermediate

Technical field

The present invention relates to the intermediate of synthesis (2R, 5R)-1,6-diphenyl hexane-2,5-diamines and salt thereof and the preparation method and application of described intermediate, belong to technical field of organic synthesis.

Background technology

The comparable west he (Cobicistat) of lucky Deco (Gilead Sciences) company exploitation is a kind of novel pharmacokinetic parameters improving inverase thus improves the synergistic agent of drug effect.This medicine itself is without HIV (human immunodeficiency virus)-resistant activity, but the Plasma Concentration by suppressing the Major Enzymes-CYP3A of human body metabolism's medicine to improve inverase.Lucky Leadd B.V have submitted new drug application on June 28th, 2012 to FDA, is now in pre-registration stage.

At International Application Serial No. PCT/US2007/015604, in publication number WO2008010921, disclose the following chemical structure of comparable west he (Cobicistat):

And from the chemical structure analysis of Cobicistat, can show that it is formed by following four fragment assemblies:

Wherein Segment A, that is: (2R, 5R)-1,6-diphenyl hexane-2,5-diamines and salt thereof be the important intermediate of the comparable west of synthesis he (Cobicistat).And for the synthesis of Segment A, what disclose in prior art is mainly following 2 routes:

Route 1(refers to described in international application WO2008010921):

This route with (S)-2-amino-3-phenyl third-1-alcohol for starting raw material, pass through oxidative coupling, remove Phenylsulfonic acid and become alkene, then reduction generates Segment A, n-Butyl Lithium is have employed in synthesis, the defect such as there is severe reaction conditions, operational difficulty, danger is high, yield is low, is not suitable for large-scale industrial production.

Route 2(refers to described in international application WO2010115000):

This route is the improvement carried out on the basis of route 1, yield is improve relative to route 1, but in synthesis, still have employed lithium reagent, there is the defect problems such as severe reaction conditions, aftertreatment difficulty, operational hazards equally, be not suitable for the demand of large-scale industrial production.

Summary of the invention

For the above-mentioned defect existing for prior art and problem, the object of this invention is to provide synthesis (2R, 5R)-1, the intermediate of 6-diphenyl hexane-2,5-diamines and salt thereof and the preparation method and application of described intermediate, to realize utilizing raw material cheap and easy to get, low cost synthesis of high purity (2R, 5R)-1, the object of 6-diphenyl hexane-2,5-diamines and salt thereof, meets the industrial production demand of comparable west he (Cobicistat).

For achieving the above object, the technical solution used in the present invention is as follows:

The intermediate of a kind of synthesis (2R, 5R)-1,6-diphenyl hexane-2,5-diamines and salt thereof, has the chemical structure of general formula shown in formula II: r in general formula is selected from the one in alkyl, the alkyl replaced by electron-withdrawing group, aryl, the aryl replaced by alkyl or electron-withdrawing group, aralkyl, heteroaryl, dialkyl amido.

As a kind of preferred version, above-mentioned alkyl is the alkyl of C1 ~ C8; Above-mentioned aryl is phenyl; Above-mentioned electron-withdrawing group is nitro or many halogen substituting group; Above-mentioned aralkyl is benzene alkyl; Above-mentioned heteroaryl is pyrryl.

As further preferred version, above-mentioned alkyl is the alkyl of C1 ~ C4; Above-mentioned many halogen substituting group is three fluoro substituents.

A method for intermediate shown in preparation formula II, comprises following reaction:

that is: formula I and sulfonylation agent are carried out sulfonylation in the basic conditions; Described sulfonylation agent is the SULPHURYL CHLORIDE of R replacement or the sulphonic acid anhydride of R replacement, and R is wherein same as above.

The intermediate of a kind of synthesis (2R, 5R)-1,6-diphenyl hexane-2,5-diamines and salt thereof, has the chemical structural formula shown in formula III:

Prepare a method for intermediate shown in formula III, comprise following reaction:

that is: that formula II intermediate is carried out in the basic conditions sulfonate group removes reaction.

Above-mentioned alkaline condition all can be formed by organic bases or mineral alkali; Described organic bases all can be selected from the one in triethylamine, diisopropyl ethyl amine, DIPEA, sodium tert-butoxide, potassium tert.-butoxide, hexamethyldisilazane lithium, 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene (DBU); Described mineral alkali all can be selected from sodium carbonate, salt of wormwood, Quilonum Retard, saleratus, sodium bicarbonate, sodium hydroxide, potassium hydroxide, the one in sodium amide.

A kind of method of intermediate synthesis (2R, 5R)-1,6-diphenyl hexane-2,5-diamines and salt thereof shown in applying equation II, comprises following reaction:

or its salt

A kind of method of intermediate synthesis (2R, 5R)-1,6-diphenyl hexane-2,5-diamines and salt thereof shown in application formula III, comprises following reaction:

or its salt

As a kind of preferred version, above-mentioned b reaction formula III intermediate is carried out catalytic hydrogenation under metal catalyst effect, production IV compound.

As further preferred version, described metal catalyst is selected from the one in palladium catalyst, rhodium catalyst, ruthenium catalyst; The hydrogen source of hydrogenation is selected from the one in hydrogen, formic acid, ammonium formiate, hydrazine, tetrahydrobenzene.

As a kind of preferred version, above-mentioned c reaction formula IV compound is carried out in acid condition tertbutyloxycarbonyl hydrolysis to remove reaction.

Described acidic conditions can be formed by organic acid or mineral acid; Described mineral acid can be selected from the one in hydrochloric acid, sulfuric acid, nitric acid; Described organic acid can be selected from the one in methanesulfonic, tosic acid, cis/trans formula butene dioic acid, succinic acid, L-TARTARIC ACID.

Formula I described in the present invention is the important intermediate of synthesis ritonavir, can be commercial and obtain, and also can be prepared by method disclosed in European patent EP 0674513, its chemical structure is as follows:

Compared with prior art, the present invention has following unusual effect:

1. apply intermediate provided by the present invention, without the need to complicated aftertreatment, just can obtain (2R, 5R)-1,6-diphenyl hexane-2,5-diamines and salt thereof that HPLC purity reaches more than 99%, and total molar yield can reach more than 80%.

2. the preparation method of described intermediate is simple, and reaction conditions is gentle, the simple easy handling of aftertreatment, and the raw material of use is cheap and easy to get, and often step molar yield all can reach more than 80%, and purity all can reach more than 90%.

In a word; the present invention can realize utilizing raw material cheap and easy to get, low cost, high yield synthesis of high purity (2R; 5R)-1; 6-diphenyl hexane-2; the object of 5-diamines and salt thereof, to realizing low cost, mass-producing prepares the significant and practical value in the comparable west of high purity he (Cobicistat).

Embodiment

Below in conjunction with embodiment, the present invention is described in further detail and completely.Formula I used in embodiment obtains with reference to the preparation of method disclosed in European patent EP 0674513, but also can be commercial.

The synthesis of embodiment 1 (2S, 3S, 5S)-5-(t-butoxycarbonyl amino)-2-(dibenzyl amino)-1,6-phenylbenzene-3-hexyl methyl sulphonate (IIa)

By formula I (10g, 17.7mmol) be dissolved in 50g methylene dichloride, add triethylamine (1.88g, 18.6mmol), be cooled to 0 ~ 10 DEG C, drip methane sulfonyl chloride (2.18g, 19.0mol), room temperature reaction to formula I disappears (TLC detects, n-hexane/ethyl acetate=5/1, V/V); Be cooled to 0 ~ 10 DEG C, reaction solution saturated sodium bicarbonate solution (50mL × 3) washing, separatory, concentrating under reduced pressure, obtains formula IIa compound 10.4g, and molar yield 91%, HPLC purity is 98.1%.

MS(ESI)m/z:M+1=643.3;

1H NMR(CDCl 3400MHz)δ1.42(m,9H),1.68(t,2H),2.80~2.92(m,4H),3.05(s,3H),3.21(s,4H),4.25(m,1H),4.93(m,1H),7.26~7.55(m,20H)。

The synthesis of embodiment 2 (2S, 3S, 5S)-5-(t-butoxycarbonyl amino)-2-(dibenzyl amino)-1,6-phenylbenzene-3-hexyl ethylsulfonic acid ester (IIb)

By formula I (10g, 17.7mmol) be dissolved in 50g tetrahydrofuran (THF), add diisopropyl ethyl amine (2.4g, 18.6mmol), be cooled to 0 ~ 10 DEG C, drip ethanesulfonyl chloride (2.44g, 19.0mol), room temperature reaction to formula I disappears (TLC detects, n-hexane/ethyl acetate=5/1, V/V); Be cooled to 0 ~ 10 DEG C, reaction solution saturated sodium bicarbonate solution (50mL × 3) washing, separatory, concentrating under reduced pressure, obtains formula IIb compound 10.2g, and molar yield 88%, HPLC purity is 96.9%.

MS(ESI)m/z:M+1=657.6;

1H NMR(CDCl 3400MHz)δ1.29(t,3H),1.43(m,9H),1.69(t,2H),2.80~2.92(m,4H),3.08(s,2H),3.24(s,4H),4.23(m,1H),4.95(m,1H),7.24~7.58(m,20H)。

The synthesis of embodiment 3 (2S, 3S, 5S)-5-(t-butoxycarbonyl amino)-2-(dibenzyl amino)-1,6-phenylbenzene-3-hexyl p-toluenesulfonic esters (IIc)

By formula I (10g, 17.7mmol) be dissolved in 100g toluene, add sodium carbonate (2.0g, 20% aqueous solution 19mmol) be made into, is cooled to-5 ~ 0 DEG C, drips Tosyl chloride (3.8g, 10g toluene solution 20.0mol), room temperature reaction to formula I disappears (TLC detects, n-hexane/ethyl acetate=5/1, V/V); Be cooled to 10 ~ 15 DEG C, reaction solution saturated sodium bicarbonate solution (50mL × 3) washing, separatory, carries out concentrating under reduced pressure to organic phase, obtains formula IIc compound 11.4g, and molar yield 90%, HPLC purity is 95.8%.

MS(ESI)m/z:M+1=720.0;

1H NMR(CDCl 3400MHz)δ1.43(m,9H),2.80~2.92(m,4H),3.08(s,2H),3.24(s,4H),4.23(m,1H),4.95(m,1H),7.22~7.61(m,24H)。

The synthesis of embodiment 4 (2S, 3S, 5S)-5-(t-butoxycarbonyl amino)-2-(dibenzyl amino)-1,6-phenylbenzene-3-hexyl phenyl sulphonate (IId)

By formula I (10g, 17.7mmol) be dissolved in 100g ethyl acetate, add salt of wormwood (2.9g, 20% aqueous solution 21mmol) be made into, is cooled to-5 ~ 0 DEG C, drips benzene sulfonyl chloride (3.7g, 10g ethyl acetate solution 19mmol), room temperature reaction to formula I disappears (TLC detects, n-hexane/ethyl acetate=5/1, V/V); Be cooled to 10 ~ 15 DEG C, reaction solution saturated sodium bicarbonate solution (50mL × 3) washing, separatory, carries out concentrating under reduced pressure to organic phase, obtains formula IId compound 11.4g, and molar yield 91%, HPLC purity is 96.7%.

MS(ESI)m/z:M+1=706.0;

1H NMR(CDCl 3400MHz)δ1.36(s,9H),1.73(t,2H),2.66~3.02(m,4H),3.24(m,1H),3.44(s,4H),3.91(m,1H),5.26(m,1H),7.25~7.61(m,20H),7.75~7.83(m,4H)。

The synthesis of embodiment 5 (2S, 3S, 5S)-5-(t-butoxycarbonyl amino)-2-(dibenzyl amino)-1,6-phenylbenzene-3-hexyl p-nitrophenyl sulphonate (IIe)

By formula I (10g, 17.7mmol) be dissolved in 100g methylene dichloride, add triethylamine (2.2g, 22mmol), be cooled to-5 ~ 0 DEG C, drip 4-Nitrobenzenesulfonyl chloride (4.65g, 20g dichloromethane solution 21mmol), room temperature reaction to formula I disappears (TLC detects, n-hexane/ethyl acetate=5/1, V/V); Be cooled to 10 ~ 15 DEG C, reaction solution saturated sodium bicarbonate solution (50mL × 3) washing, separatory, carries out concentrating under reduced pressure to organic phase, obtains formula IIe compound 12.61g, and molar yield 95%, HPLC purity is 98.7%.

MS(ESI)m/z:M+1=750.8;

1H NMR(CDCl 3400MHz)δ1.39(s,9H),1.71(t,2H),2.69~3.12(m,4H),3.20(m,1H),3.36(s,4H),3.98(m,1H),5.31(m,1H),7.25~7.61(m,20H),8.19(m,2H),8.55(m,2H)。

The synthesis of embodiment 6 (2S, 3S, 5S)-5-(t-butoxycarbonyl amino)-2-(dibenzyl amino)-1,6-phenylbenzene-3-hexyl triflate (IIf)

By formula I (10g, 17.7mmol) be dissolved in 100g Iso Butyl Acetate, add Quilonum Retard (1.63g, 10% aqueous solution 22mmol) be made into, is cooled to-5 ~ 0 DEG C, drips trifluoromethanesulfanhydride anhydride (5.92g, 20g Iso Butyl Acetate solution 21mmol), room temperature reaction to formula I disappears (TLC detects, n-hexane/ethyl acetate=5/1, V/V); Be cooled to 10 ~ 15 DEG C, reaction solution saturated sodium bicarbonate solution (50mL × 3) washing, separatory, carries out concentrating under reduced pressure to organic phase, obtains formula IIf compound 11.0g, and molar yield 89%, HPLC purity is 94.8%.

MS(ESI)m/z:M+1=697.8;

1H NMR(CDCl 3400MHz)δ1.38(s,9H),1.73(t,2H),2.69~3.12(m,4H),3.21(m,1H),3.34(s,4H),3.96(m,1H),5.32(m,1H),7.27~7.65(m,20H)。

The synthesis of embodiment 7 (2S, 3S, 5S)-5-(t-butoxycarbonyl amino)-2-(dibenzyl amino)-1,6-phenylbenzene-3-hexyl dimethylsulfamate (IIg)

By formula I (10g, 17.7mmol) be dissolved in 100g methylene dichloride, add triethylamine (2.12g, 21mmol), be cooled to-5 ~ 0 DEG C, drip dimethylaminosulfonyl chloride (2.87g, 20g dichloromethane solution 20mmol), room temperature reaction to formula I disappears (TLC detects, n-hexane/ethyl acetate=5/1, V/V); Be cooled to 10 ~ 15 DEG C, reaction solution saturated sodium bicarbonate solution (50mL × 3) washing, separatory, carries out concentrating under reduced pressure to organic phase, obtains formula IIg compound 11.5g, and molar yield 97%, HPLC purity is 96.8%.

MS(ESI)m/z:M+1=672.8;

1H NMR(CDCl 3400MHz)δ1.39(s,9H),1.74(t,2H),2.65~3.08(m,4H),3.14(s,6H),3.22(m,1H),3.33(s,4H),3.91(m,1H),5.30(m,1H),7.28~7.67(m,20H)。

The synthesis of embodiment 8 (2S, 3S, 5S)-5-(t-butoxycarbonyl amino)-2-(dibenzyl amino)-1,6-phenylbenzene-3-hexyl-1-Pyrrolidine base sulphonate (IIh)

By formula I (10g, 17.7mmol) be dissolved in 100g methylene dichloride, add triethylamine (2.22g, 22mmol), be cooled to-5 ~ 0 DEG C, drip 1-Pyrrolidine base SULPHURYL CHLORIDE (3.64g, 20g dichloromethane solution 21mmol), room temperature reaction to formula I disappears (TLC detects, n-hexane/ethyl acetate=5/1, V/V); Be cooled to 10 ~ 15 DEG C, reaction solution saturated sodium bicarbonate solution (50mL × 3) washing, separatory, carries out concentrating under reduced pressure to organic phase, obtains formula IIh compound 11.3g, molar yield 91%HPLC purity 95.5%.

MS(ESI)m/z:M+1=698.9;

1H NMR(CDCl 3400MHz)δ1.40(s,9H),1.74(t,2H),1.94(t,4H),2.63~3.07(m,4H),3.14(t,4H),3.23(m,1H),3.32(s,4H),3.92(m,1H),5.31(m,1H),7.24~7.63(m,20H)。

The synthesis of embodiment 9 (2S, 3S, 5S)-5-(t-butoxycarbonyl amino)-2-(dibenzyl amino)-1,6-phenylbenzene-3-hexyl-1-phenmethyl sulphonate (IIi)

By formula I (10g, 17.7mmol) be dissolved in 100g methylene dichloride, add triethylamine (2.22g, 22mmol), be cooled to-5 ~ 0 DEG C, drip arylsulfonyl chloride (4.0g, 20g dichloromethane solution 21mmol), room temperature reaction to formula I disappears (TLC detects, n-hexane/ethyl acetate=5/1, V/V); Be cooled to 10 ~ 15 DEG C, reaction solution saturated sodium bicarbonate solution (50mL × 3) washing, separatory, carries out concentrating under reduced pressure to organic phase, obtains formula IIi compound 11.2g, and molar yield 88%, HPLC purity is 96.5%.

MS(ESI)m/z:M+1=719.9;

1H NMR(CDCl 3400MHz)δ1.38(s,9H),1.75(t,2H),2.65~3.08(m,4H),3.25(m,1H),3.31(s,4H),3.95(m,1H),4.81(s,2H),5.31(m,1H),7.21~7.73(m,25H)。

The synthesis of embodiment 10 formula III intermediate

By (2S, 3S, 5S)-5-(t-butoxycarbonyl amino)-2-(dibenzyl amino)-1, 6-phenylbenzene-3-hexyl methyl sulphonate (IIa) (10.0g, 15.6mmol) be dissolved in 50mL tetrahydrofuran (THF), add potassium tert.-butoxide (1.8g, 16.0mmol), back flow reaction 2 hours, TLC (n-hexane/ethyl acetate=5/1, V/V) detect formula IIa compound to disappear, add 50mL saturated aqueous ammonium chloride, extract with methylene dichloride (100mL × 3), concentrating under reduced pressure is carried out to organic phase, obtain formula III compound 7.67g, molar yield 90%, HPLC purity is 95.6%.

MS(ESI)m/z:M+1=547.7;

1H NMR(CDCl 3400MHz)δ1.32(s,9H),2.85~3.18(m,4H),3.71(s,4H),4.31(m,1H),5.16(dd,1H),5.46(dd,1H),7.21~7.73(m,20H)。

The synthesis of embodiment 11 formula III intermediate

By (2S, 3S, 5S)-5-(t-butoxycarbonyl amino)-2-(dibenzyl amino)-1, 6-phenylbenzene-3-hexyl ethylsulfonic acid ester (IIb) (10.2g, 15.6mmol) be dissolved in 40mL toluene, add sodium tert-butoxide (1.5g, 16.0mmol), 55 ~ 65 DEG C are reacted 3 hours, TLC (n-hexane/ethyl acetate=5/1, V/V) detect formula IIb compound to disappear, add 50mL saturated aqueous ammonium chloride, extract with methylene dichloride (100mL × 3), concentrating under reduced pressure is carried out to organic phase, obtain formula III compound 7.52g, molar yield 88%, HPLC purity is 96.7%.

MS(ESI)m/z:M+1=547.7;

1H NMR(CDCl 3400MHz)δ1.32(s,9H),2.85~3.18(m,4H),3.71(s,4H),4.31(m,1H),5.16(dd,1H),5.46(dd,1H),7.21~7.73(m,20H)。

The synthesis of embodiment 12 formula III intermediate

By (2S, 3S, 5S)-5-(t-butoxycarbonyl amino)-2-(dibenzyl amino)-1, 6-phenylbenzene-3-hexyl p-toluenesulfonic esters (IIc) (11.5g, 16.0mmol) be dissolved in 50mL2-methyltetrahydrofuran, add DBU (1, 8-diazabicylo [5.4.0] 11 carbon-7-alkene) (2.4g, 16.0mmol), 65 ~ 70 DEG C are reacted 5 hours, TLC (n-hexane/ethyl acetate=5/1, V/V) detect formula IIc compound to disappear, add 50mL saturated aqueous ammonium chloride, extract with methylene dichloride (100mL × 3), concentrating under reduced pressure is carried out to organic phase, obtain formula III compound 7.9g, molar yield 93%, HPLC purity is 95.7%.

MS(ESI)m/z:M+1=547.7;

1H NMR(CDCl 3400MHz)δ1.32(s,9H),2.85~3.18(m,4H),3.71(s,4H),4.31(m,1H),5.16(dd,1H),5.46(dd,1H),7.21~7.73(m,20H)。

The synthesis of embodiment 13 formula III intermediate

By (2S, 3S, 5S)-5-(t-butoxycarbonyl amino)-2-(dibenzyl amino)-1, 6-phenylbenzene-3-hexyl phenyl sulphonate (IId) (11.0g, 15.6mmol) be dissolved in 50mL dimethylbenzene, add salt of wormwood (2.2g, 16.0mmol), 85 ~ 90 DEG C are reacted 3 hours, TLC (n-hexane/ethyl acetate=5/1, V/V) detect formula IId compound to disappear, add 50mL saturated aqueous ammonium chloride, extract with methylene dichloride (100mL × 3), concentrating under reduced pressure is carried out to organic phase, obtain formula III compound 7.4g, molar yield 87%, HPLC purity is 97.3%.

MS(ESI)m/z:M+1=547.7;

1H NMR(CDCl 3400MHz)δ1.32(s,9H),2.85~3.18(m,4H),3.71(s,4H),4.31(m,1H),5.16(dd,1H),5.46(dd,1H),7.21~7.73(m,20H)。

The synthesis of embodiment 14 formula III intermediate

By (2S, 3S, 5S)-5-(t-butoxycarbonyl amino)-2-(dibenzyl amino)-1, 6-phenylbenzene-3-hexyl p-nitrophenyl sulphonate (IIe) (11.7g, 15.6mmol) be dissolved in 50mL N, in dinethylformamide, add sodium carbonate (1.7g, 16.0mmol), 75 ~ 80 DEG C are reacted 2 hours, TLC (n-hexane/ethyl acetate=5/1, V/V) detect formula IIe compound to disappear, add 50mL saturated aqueous ammonium chloride, extract with methylene dichloride (100mL × 3), concentrating under reduced pressure is carried out to organic phase, obtain formula III compound 7.0g, molar yield 82%, HPLC purity is 93.3%.

MS(ESI)m/z:M+1=547.7;

1H NMR(CDCl 3400MHz)δ1.32(s,9H),2.85~3.18(m,4H),3.71(s,4H),4.31(m,1H),5.16(dd,1H),5.46(dd,1H),7.21~7.73(m,20H)。

The synthesis of embodiment 15 formula III intermediate

By (2S, 3S, 5S)-5-(t-butoxycarbonyl amino)-2-(dibenzyl amino)-1, 6-phenylbenzene-3-hexyl triflate (IIf) (10.8g, 15.6mmol) be dissolved in 50mL tetrahydrofuran (THF),-50 ~-40 DEG C drip hexamethyldisilazane lithium (2.6g, 16.0mmol), 0 ~ 10 DEG C is kept to react 6 hours, TLC (n-hexane/ethyl acetate=5/1, V/V) detect formula IIf compound to disappear, add 50mL saturated aqueous ammonium chloride, extract with methylene dichloride (100mL × 3), concentrating under reduced pressure is carried out to organic phase, obtain formula III compound 8.0g, molar yield 94%, HPLC purity is 98.3%.

MS(ESI)m/z:M+1=547.7;

1H NMR(CDCl 3400MHz)δ1.32(s,9H),2.85~3.18(m,4H),3.71(s,4H),4.31(m,1H),5.16(dd,1H),5.46(dd,1H),7.21~7.73(m,20H)。

The synthesis of embodiment 16 formula III intermediate

By (2S, 3S, 5S)-5-(t-butoxycarbonyl amino)-2-(dibenzyl amino)-1, 6-phenylbenzene-3-hexyl dimethylsulfamate (IIg) (10.4g, 15.6mmol) be dissolved in 50mL tetrahydrofuran (THF), add sodium amide (0.6g, 16.0mmol), 30 ~ 40 DEG C are reacted 1 hour, TLC (n-hexane/ethyl acetate=5/1, V/V) detect formula IIg compound to disappear, add 50mL saturated aqueous ammonium chloride, extract with methylene dichloride (100mL × 3), concentrating under reduced pressure is carried out to organic phase, obtain formula III compound 7.1g, molar yield 83%, HPLC purity is 95.2%.

MS(ESI)m/z:M+1=547.7;

1H NMR(CDCl 3400MHz)δ1.32(s,9H),2.85~3.18(m,4H),3.71(s,4H),4.31(m,1H),5.16(dd,1H),5.46(dd,1H),7.21~7.73(m,20H)。

The synthesis of embodiment 17 formula III intermediate

By (2S, 3S, 5S)-5-(t-butoxycarbonyl amino)-2-(dibenzyl amino)-1, 6-phenylbenzene-3-hexyl-1-pyrryl sulphonate (IIh) (10.8g, 15.6mmol) be dissolved in 50mL toluene, add DBU (1, 8-diazabicylo [5.4.0] 11 carbon-7-alkene) (2.4g, 16.0mmol), 80 ~ 90 DEG C are reacted 8 hours, TLC (n-hexane/ethyl acetate=5/1, V/V) detect formula IIh compound to disappear, add 50mL saturated aqueous ammonium chloride, extract with methylene dichloride (100mL × 3), concentrating under reduced pressure is carried out to organic phase, obtain formula III compound 7.9g, molar yield 93%, HPLC purity is 96.5%.

MS(ESI)m/z:M+1=547.7;

1H NMR(CDCl 3400MHz)δ1.32(s,9H),2.85~3.18(m,4H),3.71(s,4H),4.31(m,1H),5.16(dd,1H),5.46(dd,1H),7.21~7.73(m,20H)。

The synthesis of embodiment 18 formula III intermediate

By (2S, 3S, 5S)-5-(t-butoxycarbonyl amino)-2-(dibenzyl amino)-1, 6-phenylbenzene-3-hexyl-1-phenmethyl sulphonate (IIi) (11.2g, 15.6mmol) be dissolved in 50mL N, in dinethylformamide, add sodium hydroxide (0.64g, 16.0mmol), 40 ~ 50 DEG C are reacted 5 hours, TLC (n-hexane/ethyl acetate=5/1, V/V) detect formula IIi compound to disappear, add 50mL saturated aqueous ammonium chloride, extract with methylene dichloride (100mL × 3), concentrating under reduced pressure is carried out to organic phase, obtain formula III compound 6.9g, molar yield 81%, HPLC purity is 97.5%.

MS(ESI)m/z:M+1=547.7;

1H NMR(CDCl 3400MHz)δ1.32(s,9H),2.85~3.18(m,4H),3.71(s,4H),4.31(m,1H),5.16(dd,1H),5.46(dd,1H),7.21~7.73(m,20H)。

The synthesis of amino-1, the 6-phenylbenzene-2-carbamate (IV) of embodiment 19 (2R, the 5R)-tertiary butyl-5-

Formula III compound is dissolved in the methyl alcohol of 3 times of weight, adds 5% palladium carbon (0.1 times of weight amounts to 5% dry palladium carbon), after inert gas replacement, be filled with hydrogen pressure 0.2 ~ 1.0MPa, be incubated 25 ~ 50 DEG C of reactions 5 ~ 20 hours; When HPLC detection reaction is complete, filter, to mother liquor concentrating under reduced pressure, obtain formula IV compound, molar yield 95%, HPLC purity is 97.4%.

MS(ESI)m/z:M+1=369.2。

The synthesis of amino-1, the 6-phenylbenzene-2-carbamate (IV) of embodiment 20 (2R, the 5R)-tertiary butyl-5-

Formula III compound is dissolved in the ethanol of 3 times of weight, adds 10% palladium-carbon catalyst (0.05 times of weight amounts to 5% dry palladium carbon), after inert gas replacement, be filled with hydrogen pressure 0.2 ~ 1.0MPa, be incubated 25 ~ 50 DEG C of reactions 5 ~ 20 hours; When HPLC detection reaction is complete, filter, to mother liquor concentrating under reduced pressure, obtain formula IV compound, molar yield 97%, HPLC purity is 97.8%.

MS(ESI)m/z:M+1=369.2。

The synthesis of amino-1, the 6-phenylbenzene-2-carbamate (IV) of embodiment 21 (2R, the 5R)-tertiary butyl-5-

Formula III compound is dissolved in the Virahol of 5 times of weight, adds 5% ruthenium C catalyst (0.05 times of weight amounts to 5% dry ruthenium carbon), after inert gas replacement, be filled with hydrogen pressure 0.1 ~ 1.0MPa, be incubated 25 ~ 40 DEG C of reactions 5 ~ 20 hours; When HPLC detection reaction is complete, filter, to mother liquor concentrating under reduced pressure, obtain formula IV compound, molar yield 95%, HPLC purity is 96.6%.

The synthesis of amino-1, the 6-phenylbenzene-2-carbamate (IV) of embodiment 22 (2R, the 5R)-tertiary butyl-5-

Formula III compound is dissolved in the methyl alcohol of 5 times of weight, adds 5% rhodium C catalyst (0.05 times of weight amounts to 5% dry rhodium carbon), after inert gas replacement, be filled with hydrogen pressure 0.1 ~ 1.0MPa, be incubated 25 ~ 30 DEG C of reactions 5 ~ 10 hours; When HPLC detection reaction is complete, filter, to mother liquor concentrating under reduced pressure, obtain formula IV compound, molar yield 93%, HPLC purity is 98.2%.

The synthesis of embodiment 23 (2R, 5R) 1,6-phenylbenzene-2,5-hexamethylene-diamine hydrochloride

Formula IV compound is dissolved in dichloromethane solution, drips the 25%HCl/ methanol solution of 2.05 equivalents, separate out white solid, filter, filter cake vacuum-drying, obtains (2R, 5R)-1,6-phenylbenzene-2,5-hexamethylene-diamine hydrochloride, molar yield 95%, HPLC purity is 99.5%.

The synthesis of embodiment 24 (2R, 5R)-1,6-phenylbenzene-2,5-hexanediamine methane sulfonates

Formula IV compound is dissolved in dichloromethane solution, drip the 10% methanesulfonic/dichloromethane solution of 2.05 equivalents, separate out white solid, filter, filter cake vacuum-drying, obtain (2R, 5R) 1,6-phenylbenzene-2,5-hexanediamine methane sulfonates, molar yield 97%, HPLC purity is 99.6%.

The synthesis of embodiment 25 (2R, 5R) 1,6-phenylbenzene-2,5-hexanediamine L-TARTARIC ACID salt

Formula IV compound is dissolved in dichloromethane solution, add the L-TARTARIC ACID of 1.05 equivalents, separate out white solid, stir and separate out solid, filter, filter cake vacuum-drying, obtains (2R, 5R)-1,6-phenylbenzene-2,5-hexanediamine L-TARTARIC ACID salt, molar yield 91%, HPLC purity is 99.3%.

Embodiment 26 is from IIa one pot process (2R, 5R) 1,6-phenylbenzene-2,5-hexamethylene-diamine hydrochloride

IIa compound (6.4g, 10mmol) is dissolved in 50mL tetrahydrofuran (THF), adds potassium tert.-butoxide (1.2g, 11mmol), under protection of inert gas, 50 ~ 70 DEG C are reacted 3 hours, cooling reaction solution, adds 10% palladium-carbon catalyst, after hydrogen exchange, fill hydrogen 0.2 ~ 1.0MPa, react 5 ~ 10 hours, when HPLC detects raw material completely dissolve, filter, to mother liquor concentrating under reduced pressure, obtain formula IV compound; Dissolve enriched material with methylene dichloride, drip the 25%HCl/ methanol solution of 2.05 equivalents, separate out white solid, filter, obtain (2R, 5R) 1,6-phenylbenzene-2,5-hexamethylene-diamine hydrochloride 2.9g, molar yield 84%, HPLC purity is 99.7%.

Finally be necessary to herein means out: above embodiment is only for being further described technical scheme of the present invention; can not be interpreted as limiting the scope of the invention, some nonessential improvement that those skilled in the art's foregoing according to the present invention is made and adjustment all belong to protection scope of the present invention.

Claims (10)

1. the intermediate of synthesis (2R, 5R)-1,6-diphenyl hexane-2, a 5-diamines and salt thereof, is characterized in that having the chemical structure of general formula shown in formula II: r in general formula is selected from the one in alkyl, the alkyl replaced by electron-withdrawing group, aryl, the aryl replaced by alkyl or electron-withdrawing group, aralkyl, dialkyl amido.
2. prepare a method for intermediate described in claim 1, it is characterized in that, comprise following reaction:
that is: formula I and sulfonylation agent are carried out sulfonylation in the basic conditions; Described sulfonylation agent is the SULPHURYL CHLORIDE of R replacement or the sulphonic acid anhydride of R replacement, and R wherein as described in the appended claim 1.
3. the intermediate of synthesis (2R, 5R)-1,6-diphenyl hexane-2, a 5-diamines and salt thereof, is characterized in that having the chemical structural formula shown in formula III:
4. prepare a method for intermediate described in claim 3, it is characterized in that, comprise following reaction:
that is: that formula II intermediate is carried out in the basic conditions sulfonate group removes reaction.
5. the method for intermediate synthesis (2R, 5R)-1,6-diphenyl hexane-2,5-diamines and salt thereof described in an application rights requirement 1, is characterized in that, comprise following reaction:
or its salt.
6. the method for intermediate synthesis (2R, 5R)-1,6-diphenyl hexane-2,5-diamines and salt thereof described in an application rights requirement 3, is characterized in that, comprise following reaction:
or its salt.
7. the method as described in claim 5 or 6, is characterized in that: described b reaction formula III intermediate is carried out catalytic hydrogenation under metal catalyst effect, production IV compound.
8. method as claimed in claim 7, is characterized in that: described metal catalyst is selected from the one in palladium catalyst, rhodium catalyst, ruthenium catalyst; The hydrogen source of hydrogenation is selected from the one in hydrogen, formic acid, ammonium formiate, hydrazine, tetrahydrobenzene.
9. the method as described in claim 5 or 6, is characterized in that: described c reaction formula IV compound is carried out in acid condition tertbutyloxycarbonyl hydrolysis to remove reaction.
10. method as claimed in claim 9, is characterized in that: described acidic conditions is formed by organic acid or mineral acid; Described mineral acid is selected from the one in hydrochloric acid, sulfuric acid, nitric acid; Described organic acid is selected from the one in methanesulfonic, tosic acid, cis/trans formula butene dioic acid, succinic acid, L-TARTARIC ACID.
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