CN1951916A

CN1951916A - Process for preparing argatroban intermediates

Info

Publication number: CN1951916A
Application number: CN 200610129331
Authority: CN
Inventors: 宋洪海
Original assignee: Tianjin Weijie Technology Co Ltd
Current assignee: Tianjin Weijie Technology Co Ltd
Priority date: 2006-11-10
Filing date: 2006-11-10
Publication date: 2007-04-25
Anticipated expiration: 2026-11-10
Also published as: CN100465161C

Abstract

The invention discloses a preparing method of Argatroban intermediate, which is characterized by the following: adopting NG-nitro-N2-tBoc -L-arginine and (2R,4R)-4-methyl-2-piperidine ethyl formate to condensate; making DCC as dehydrant; reacting under -5-35deg.c for 1-5h and stirring; cooling reacting liquid; filtering to remove solid; stratifying filtrate; removing water layer; washing organic layer through sodium hydroxide solution, citrate solution and saturated salt water; drying; evaporating dichloromethane; obtaining yellow solid product.

Description

The argatroban intermediates preparation

Technical field

The present invention relates to a kind of method for preparing the argatroban intermediate.

Technical background:

The Japanese Mitsubishi S.Okamoto of chemical company in 1978 etc. have reported argatroban (Argatroban) mono-hydrate antithrombin activity [US 4 101 653] first.During more than 20 year subsequently, numerous investigators further investigate to the biological activity of Argatroban and as the value of medicine.1981, S.Okamoto compared [Okamoto, S.et al., Biochem.Biophys.Res.Commun.101,440 (1981)] in animal body with heparin; T.Kumoto etc. have carried out reporting [Kumada, T.et al., Thromb.Res.24,285 (1981)] to its three-dimensional activity of selecting; 1984, R.Kumato carried out the clinical blood dialysis and has estimated [Biochemistry 23,85 (1984) for Kikumoto, R.et al.]; This author in 1986 has reported Argatroban and has suppressed the Mammals thrombin activity, can be used as treatment and pre-preventing thrombosis medicament and platelet aggregation inhibitor.The monohydrate of Argatroban can be used as [JP 61-48829] such as selectivity antithrombotic agent, the obstruction of treatment chronic arterial and cerebral thrombosiss.1992 and 1993, Taparelli and J.A.Jakubowski successively reported reversibility [Taparelli, C., Trends Pharmacol.Sci., 1993 of Argatroban antithrombin, 14,366, Jakubowski, J.A.et al, Rep.Med.Chem., 1992,27,99]; The nineties, multidigit investigator such as L.R.Buch reported correlative study [Buch, L.R., Cadiosvasc.Drug Rev., 1991,9,247, Stmpcnewski, J.D.et al., Academic:San Diego, 1991; Vol.26, p299, Brundish, D.et al., J.Med.Chem.1999; 42,4584, Shebuski, R.J., Academic:San Diego.1999; Vol.26, p98].Japan's approval in 1992 is used antithrombin medicament [Hijikata-Okunomiya, A., et al, Thromb.Hemostasis, 1992,18, l35] as non-enteron aisle.

The chemical name of argatroban: (2R, 4R)-1-[(2S)-5-[(Aminoiminomethyl) amino]-1-oxo-2-[[(1,2,3.4-tetrahydro-3-methyl-8-quinolinyl) sulfonyl] amino] pentyl]-4-methyl-2-piperidinecarboxylic acid, its chemical ingredients is the mixture of 21 (R) and 21 (S), 64～65:36～35[US 6 440 417 normally, Cossy.J., et al, Bioorganic﹠amp; Medicine Chemistry Letters, 11 (2001), 1989-1992, Journal ofPharmaceutical Sciences, Vol.82, No.6,672 (1993)], its structural formula is:

Ia?X＝H，Y＝CH3，21-(R)-Argatroban

I?Argagroban(21(R)：21(S)＝65：35) Ib?X＝CH3，Y＝H，21-(S)-Argatroban

Now Bao Dao Argatroban (argatroban) synthetic route all be with nitro-L-arginine be starting raw material, with piperidine carboxylic acid ester or quinoline sulfuryl chloride condensation precedence difference, constitute two main routes.When at first with the piperidine carboxylic acid ester condensation, claim the amido protecting method: the arginic amino of nitro-L-with the t-Boc protection, again with the piperidine carboxylic acid ester condensation, go the Boc protecting group, go nitro to get Argatroban with quinoline sulfuryl chloride condensation, ester hydrolysis, hydrogenation.If claim non-protection method during at first with the quinoline sulfuryl chloride condensation: go nitro to get target product with piperidine carboxylic acid ester condensation, ester hydrolysis, hydrogenation again after nitro arginine and the quinoline sulfuryl chloride condensation.Comprise specifically:

The amido protecting method:

1. nitro arginine t-Boc protection back and (2R, 4R) piperidine carboxylic acid ester condensation [EP 8746, and US 4258192, US4201863, JP 81-15,267, US 6440417, the flat 2-31055 of special permission communique].Reaction scheme such as Fig. 1.

Nitro arginine t-Boc protection back with trans piperidine carboxylic acid ester condensation, separate, split, again with quinoline sulfuryl chloride condensation [Cossy.J., et al, Bioorganic ﹠amp; Medicine Chemistry Letters, 11 (2001), 1989-1992].Concrete reaction scheme such as Fig. 2.

Non-protection method:

When the L-arginine during directly with the quinoline sulfuryl chloride condensation byproduct of reaction many, not easily separated, be not suitable for suitability for industrialized production [speciallyying permit the flat 1-35000 of communique].Nitro-reactor product was single when the L-arginine was raw material, operated simple and easyly, was suitable for suitability for industrialized production [EP 823 430].Concrete reaction scheme such as Fig. 3.

Ethyl (2R, 4R)-1-[N ^G-nitro-N ²-(tert-butoxycarbonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylate (I) is the key intermediate that the amido protecting legal system is equipped with Argatroban; [EP 8746 for reported in literature; US 4258192]; with nitro-L-arginine is raw material; with the reaction of dimethyl dicarbonate butyl ester, be converted into N ^G-nitro-N ²-tBoc-L-arginine then with the isobutyl chlorocarbonate reaction, generates corresponding acid anhydrides, with (2R, 4R)-4-methyl-Pipecolic Acid ethyl ester reaction, generate Compound I, two-step reaction is all incomplete after this method, contains the first two steps raw material in the product, not easily separated purification, require low temperature-20～-25 ℃, reagent isobutyl chlorocarbonate toxicity is big, need prepare from phosgene, the source is restricted, shortcomings such as operational condition is poor, and productive rate is low, its reaction is as follows:

Summary of the invention

The purpose of this invention is to provide a kind of argatroban intermediates preparation.The present invention is on the basis of various synthetic routes, and the amido protecting method has been carried out important improvement.Adopt DCC (N, N-dicyclohexylcarbodiimide) dehydrating condensation, single step reaction, simple to operate, mild condition, yield height, product quality are good, easily suitability for industrialized production.

Argatroban intermediates preparation provided by the invention comprises:

Adopt N ^G-nitro-N ²-tBoc-L-arginine with (2R, 4R)-4-methyl-Pipecolic Acid ethyl ester condensation, as dewatering agent, its reaction is as follows with DCC:

Concrete step:

In dichloromethane solvent, add successively (2R, 4R)-4-methyl-Pipecolic Acid ethyl ester, DCC and N ^G-nitro-N ²-tBoc-L-arginine, at-5～35 ℃ of following stirring reaction 1-5 hours, reaction finished.Add 50ml water, stirred 0.5-1 hour, and reaction solution was chilled to 0 ℃, solids removed by filtration, the filtrate layering, remove water layer, organic layer is used 5-10% sodium hydroxide solution washed twice respectively, washes once with the 5-10% citric acid solution, use the saturated common salt water washing again, anhydrous sodium sulfate drying steams methylene dichloride, gets yellow solid product.

Reactant (2R, 4R)-4-methyl-Pipecolic Acid ethyl ester and N ^G-nitro-N ²The arginic mol ratio of-tBoc-L-1: 1.0～1.2;

The mol ratio of reactant and DCC 1: 1～1.05;

The weight ratio of reactant and methylene dichloride 1: 20～50.

Argatroban intermediates preparation provided by the invention is that one step of document amido protecting method two-step reaction is finished, and raw material DCC safety is easy to get, and is simple to operate; react completely, temperature of reaction-5～35 ℃, yield brings up to 85～90%; product (intermediate compound I) is easily purified, easily suitability for industrialized production.

Description of drawings

Fig. 1 nitro arginine t-Boc protection back and (2R, 4R) piperidine carboxylic acid ester condensation reaction route diagram.

Fig. 2 nitro arginine t-Boc protection back with trans piperidine carboxylic acid ester condensation, separate, split, illustrate with quinoline sulfuryl chloride condensation reaction route again.

The non-protection method reaction scheme diagram of Fig. 3.

Embodiment

Embodiment 1.N ^GThe arginic preparation of-nitro-L-

Add the 165 gram vitriol oils in the 300ml four-hole reaction flask, stir and add 34.8 gram (0.2mol) L-arginine down, be stirred to transparently, add 20.0 gram (0.4mol) ammonium nitrate, stirring at room reaction 3 hours.The reaction end in the frozen water with reaction solution impouring 600 grams, neutralizes with about 370 gram ammoniacal liquor (17%), and control pH6.5 separates out white solid, and filtration, washing are with getting N behind the 900 gram water recrystallizations ^G-nitro-L-arginine 35.7 grams, content 98.5% (HPLC quantitative analysis method), yield 80.3%.

Embodiment 2.N ^G-nitro-N ²The arginic preparation of-tBoc-L-

Add 100ml water in the 300ml four-hole reaction flask, stir 4.4 gram (1.1mol) sodium hydroxide of adding down, the stirring and dissolving postcooling adds 20.0 gram (0.091mol) N ^G-nitro-L-the arginine and the 52 gram trimethyl carbinols stir a moment, get clear solution, ℃ adding 25.9 gram (0.119mol) dimethyl dicarbonate butyl esters in liquid temperature＜10, and stirring at room 16 hours, reaction solution pH is 8.Add the 450ml sherwood oil, stir, standing demix divides and removes sherwood oil, water adds the 200ml methyl tertiary butyl ether, stirs cooling and drips 14.5 gram concentrated hydrochloric acids down, and regulating pH is 1.5, continues to stir, separate out white solid, filter, methyl tertiary butyl ether washing, the dry 17.4 gram N that get ^G-nitro-N ²-tBoc-L-arginine (HPLC quantitative analysis method), content 96.5%, yield 57.8%.

Embodiment 3. (2R, 4R)-1-(N ^G-nitro-N ²-(tertiary butyl oxygen base carbonyl)-L-arginine)-4

The preparation of-methyl-Pipecolic Acid ethyl ester

In the 5000ml four-hole reaction flask, add the 3000ml methylene dichloride, stir down, add (2R, 4R)-4-methyl-Pipecolic Acid ethyl ester 112.8g (0.655mol), all dissolvings in about 0.5 hour.Under the stirring at room, add DCC134.8 gram (0.655mol), continue to stir 0.5 hour, add N ^G-nitro-N ²-tBoc-L-arginase 12 09.0 gram (0.655mol), stirring at room 2 hours, TLC detected (solvent systems is an ethyl acetate), and raw material disappears substantially, the reaction end.Add 600ml water, stirred 0.5 hour, reaction solution is chilled to 0 ℃, remove by filter the by product urea, water layer is removed in the filtrate layering, organic layer to neutral, is used the water washing of 600ml saturated common salt with the washing of 600ml10% citric acid solution with 950ml10% sodium hydroxide solution washed twice again, anhydrous sodium sulfate drying, normal pressure steams methylene dichloride, and decompression at last removes residual methylene dichloride, gets yellow solid 280.4 grams, content: 98.3% (HPLC quantitative analysis method), yield: 89.0%.

Embodiment 4.

In the 5000ml four-hole reaction flask, add the 250ml methylene dichloride, stir down, add (2R, 4R)-4-methyl-Pipecolic Acid ethyl ester 17.2g (0.1mol), stir and make its dissolving, add DCC25 gram (0.12mol), stir after 0.5 hour, add N ^G-nitro-N ²-tBoc-L-arginine 32 grams (0.1mol) stirred 4 hours at 0～-5 ℃, and TLC detects, and raw material disappears substantially, and reaction finishes.Add 50ml water, stirred 1 hour, reaction solution is chilled to about 0 ℃, solids removed by filtration, water layer is removed in the filtrate layering, organic layer 50ml5% sodium hydroxide solution washed twice, wash once with the 50ml10% citric acid solution, use the water washing of 50ml saturated common salt again, anhydrous sodium sulfate drying, remove methylene dichloride, get yellow solid 41.9 grams, content: 98.7% (HPLC quantitative analysis method), yield: 87.5%.

The comparative example

100ml four-hole reaction flask adds 50ml THF and 3.2 gram nitro arginine (0.06mol), stir a muddy liquid.The liquid temperature is chilled to-15～-20 ℃, drips 1 gram (0.01mol) triethylamine, drip 1.3 gram (0.01mol) isobutyl chlorocarbonates again, under this temperature, reacted 10 minutes then, and dropping 1.72 grams (0.01mol) (2R, 4R)-4-methyl piperidine ethyl formate.The liquid temperature rise is to room temperature after 10 minutes, and stirring is spent the night, and reaction finishes.Removal of solvent under reduced pressure, add 65ml ethyl acetate and 25ml water, solid is complete to leave standstill after molten, layering, remove water layer, ethyl acetate layer with the 15ml5% sodium carbonate solution wash, the 15ml10% citric acid solution is washed, 25ml washing back anhydrous sodium sulfate drying, decompression removes solvent, get yellow oil, weight 2.12 grams, content 97.8% (HPLC quantitative analysis method), yield 45.6%.

Claims

1, a kind of argatroban intermediates preparation is characterized in that it is to adopt N ^G-nitro-N ²-tBoc-L-arginine with (2R, 4R)-4-methyl-Pipecolic Acid ethyl ester condensation, as dewatering agent, its reaction is as follows with DCC:

Concrete step:

2, method according to claim 1, it is characterized in that described reactant (2R, 4R)-4-methyl-Pipecolic Acid ethyl ester and N ^G-nitro-N ²The arginic mol ratio of-tBoc-L-: 1: 1.0～1.2.

3, method according to claim 1 is characterized in that the mol ratio 1: 1～2 of described reactant and DCC.

4, method according to claim 1 is characterized in that the weight ratio 1: 20～50 of described reactant and methylene dichloride.