Synthesis of midodrine HCI from a novel intermediate...

Details Synthesis of midodrine HCI from a novel intermediate... Synthesis of midodrine HCI from a novel intermediate...

2000-04-17

2001-03-13

Barts, Samuel (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C552S010000

Reexamination Certificate

active

06201153

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to the synthesis of midodrine hydrochloride, ±1-(2′,5′-dimethoxyphenyl)-2-glycineamido-ethanol-(1)-HCl, from a novel intermediate, 1-(2′,5′-dimethoxyphenyl)-2-azidoethanone.
The compound midodrine is part of the class of compounds known as phenylalkanolamine derivatives which have been found to be effective in treating hypertensive conditions due to their long lasting blood pressure increasing effect.
SUMMARY OF THE INVENTION
The objective of the present disclosure is to provide novel synthetic strategies to prepare midodrine HCl from a novel intermediate, 1-(2′,5′-dimethoxyphenyl)-2-azidoethanone. The synthetic routes of the present invention provide increased yields and minimized by-products, which therefore also minimizes expenses.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to the synthesis of midodrine hydrochloride, ±1-(2′,5′-dimethoxyphenyl)-2-glycineamido-ethanol-(1)-HCl. The synthetic route comprises reduction of the intermediate, 1-(2′,5′-dimethoxyphenyl)-2-azidoethanone (Compound II) to produce the compound ±1-(2′,5′-dimethoxyphenyl)-2-glycineamido-ethanol-(1)-HCl (Compound I).
The novel intermediate, 1-(2′,5′-dimethoxyphenyl)-2-azidoethanone (Compound II) is prepared by acylating the compound 1,4-dimethoxybenzene (Compound III) by a Friedel-Crafts reaction with haloacetylchloride or haloaceticanhydride and anhydrous aluminum chloride in the presence of a chlorinated organic solvent. Halo includes chloro, bromo, and the like. Examples of haloacetylchlorides include chloroacetylchloride and bromoacetylchlorides. Examples of haloacetic anhydrides include chloro-acetic anhydride and bromo-acetic anhdyride. Examples of chlorinated organic solvents are methylenechloride and dichloroethane. Carbon disulfide may also be used as a solvent. The product, 1-(2′,5′-dimethoxyphenyl)-2-haloethanone (Compound IV), is obtained in pure form; only one isomer is obtained as all the four positions of benzene nucleus are equivalent. This step is shown schematically as follows, with X representing halo, preferably chloro:
Step 1
The intermediate, Compound II, is prepared by introducing an azide group to replace halo from the &agr;-position in Compound IV. The halogen containing carbon is highly activated by the presence of the adjacent carbonyl group and is therefore easily replaced. This reaction is carried out in nitrogen purged 60% acetone-water mixture. This step is shown schematically as follows:
Step 2
This novel ketoazide compound, 1-(2′,5′-dimethoxyphenyl)-2-azidoethanone (Compound II), is used as an intermediate for the synthesis of 1-(2′,5′-dimethoxyphenyl)-2-glycineamidoethanol-(1) HCl (Compound I).
The introduction of the azido group into Compound II allows the carbonyl and the azide to be reduced simultaneously in one pot. This provides an improvement to the process in that fewer process steps are needed. Therefore in the next step, the keto and the azide groups are both reduced to produce ±1-(2′,5′-dimethoxyphenyl)-2-aminoethanol (Compound V), a known metabolite of midodrine. The reduction may be by any known method using known reducing agents including reduction by lithium aluminum hydride (LiAlH
4
) in tetrahydrofuran, or reduction by sodium borohydride in tetrahydrofuran or a mixture of tetrahydrofuran and methanol, or by hydrogenation in the presence of Pd/C (10%) with methanol, ethanol or a mixture of organic solvents. This reaction step is shown as follows:
Step 3
In conventional amidation reactions, the aminoethanol, Compound V, produced in the above step may be reacted with N-carbo-t-butoxyglycine-amido (N-BOC-Glycine) in the presence of dicyclohexylcarbodiimide (DCC) to form an amide bond. However, if DCC is used simultaneously with aminoethanol, Compound V, and N-BOC-Glycine in situ, the yield is poor due to the generation of by-products. Moreover, one of the by-products, dicyclohexylurea, DCU, becomes trapped and remains in the product.
It has been found, in accordance with the present invention, that this problem with DCU could be avoided. In the synthetic reaction of the present invention a pure anhydride was synthesized by reacting N-BOC-glycine with DCC, in a 2:1 ratio, in dry methylene chloride. The DCU thus formed is precipitated out at 0° C. to provide exclusively N-BOC-glycine anhydride, Compound VI, in the solution. The pure anhydride was thus obtained:
Step 4
In the above reaction scheme, RT signifies ambient temperature.
The anhydride produced according to Step 4, Compound VI, was then reacted with the amine group of the aminoalcohol, Compound V, in the presence of 4,4′-dimethylaminopryidine, DMAP, a catalyst found to be very effective in reducing the reaction time and increasing the yield of the product, 1-(2′,5′-dimethoxyphenyl)-2-(N-carbo-t-butoxyglycine-amido)-ethanol-(1), Compound VII.
Step 5
The 1-(2′,5′-dimethoxyphenyl)-2-(N-carbo-t-butoxyglycine-amido)-ethanol-(1) compound, Compound VII, produced in Step 5 is subjected to any polar protic or aprotic solvent to yield the desired ±1-(2′,5′-dimethoxyphenyl)-2-glycineamido-ethanol-(1)-hydrochloride, Compound I. Examples of polar protic or aprotic solvents include acetone/aq. HCl or HCl gas/MeOH or 3M HCl—EtOAc.
Step 6


REFERENCES:
patent: 3340298 (1967-09-01), Wismayr et al.
patent: 241435 (1965-07-01), None
Rammler et al., “Studies on Polynucleotides. XX. Amino Acid Acceptor Ribonucleic Acids. The Synthesis and Properties of 2′(or 3′))-0-(DL-Phenylalanyl)-adeonsine, 2′(or 3′)-0-(DL-Phenylalanyl)-uridine and Related Compounds”, J. Am. Chem. Soc., vol. 85, p. 1997-2002 (1963).
Jonas et al., “The Use of Midodrin in the Treatment of Ejaculation Disorders following Retroperitoneal Lymphadenectomy”, Eur. Urol., vol. 5, pp. 184-187 (1979).
Soai et al., “Reduction of Azides to Amines with Sodium Borohydride in Tetrahydrofuran with Dropwise Addition of Methanol”, Synth. Commun., pp. 48-49, (1986).

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