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METHYL DOPA

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ChemSpider 2D Image | L-Methyldopa | C10H13NO4

L-Methyldopa

  • Molecular FormulaC10H13NO4
  • Average mass211.214 Da
Name : Methyldopa
Synonym : 3-hydroxy-alpha-methyl-L-tyrosine
Mol Formula : C10H13NO4
CAS : 555-30-6
(S)-(-)-α-Methyldopa
L-Methyldopa
(-)-Methyldopa
(-)-α-Methyldopa
(S)-(-)-a-Methyldopa
(S)-a-Methyldopa
1110
209-089-2 [EINECS]
2417244
3-(3,4-Dihydroxyphenyl)-2-methyl-L-alanine
3-Hydroxy-α-methyl-L-tyrosine
555-30-6 [RN],
Alanine, 3- (3,4-dihydroxyphenyl)-2-methyl-, L-

Synthesis ReferenceVincenzo Cannata, Giancarlo Tamerlani, Mauro Morotti, “Process for the synthesis of the levodopa.” U.S. Patent US4962223, issued December, 1986.

US4962223

Methyldopa USP is the L-isomer of alpha-methyldopa. Its chemical name is levo-3-(3,4-dihydroxyphenyl)- 2-methylalanine sesquihydrate. Its structural formula is:

Methyldopa structural formula

10H13NO4 • 1 1/2 H2O M.W. 238.24

Levodopa is a prodrug of dopamine that is administered to patients with Parkinson’s due to its ability to cross the blood-brain barrierLabel. Levodopa can be metabolised to dopamine on either side of the blood-brain barrier and so it is generally administered with a dopa decarboxylase inhibitor like carbidopa to prevent metabolism until after it has crossed the blood-brain barrierLabel,1. Once past the blood-brain barrier, levodopa is metabolized to dopamine and supplements the low endogenous levels of dopamine to treat symptoms of Parkinson’sLabel. The first developed drug product that was approved by the FDA was a levodopa and carbidopa combined product called Sinemet that was approved on May 2, 19751,7.

Methyldopa, sold under the brand name Aldomet among others, is a medication used for high blood pressure.[1] It is one of the preferred treatments for high blood pressure in pregnancy.[1] For other types of high blood pressure including very high blood pressure resulting in symptoms other medications are typically preferred.[1] It can be given by mouth or injection into a vein.[1] Onset of effects is around 5 hours and they last about a day.[1]

Common side effects include sleepiness.[1] More severe side effects include red blood cell breakdown, liver problems, and allergic reactions.[1] Methyldopa is in the alpha-2 adrenergic receptor agonist family of medication.[1] It works by stimulating the brain to decrease the activity of the sympathetic nervous system.[1]

Methyldopa was discovered in 1960.[2] It is on the World Health Organization’s List of Essential Medicines, the most effective and safe medicines needed in a health system.[3] The wholesale cost in the developing world is about US$4.31–9.48 per month.[4] In the United States it costs less than $25 per month.[5]

Medical uses

Methyldopa is used in the clinical treatment of the following disorders:

Side effects

Methyldopa is capable of inducing a number of adverse side effects, which range from mild to severe. Nevertheless, they are generally mild when the dose is less than 1 gram per day.[6] Side effects may include:

Rebound/withdrawal

Rebound hypertension via withdrawal on account of tolerance upon the abrupt discontinuation of methyldopa has been reported.[7]

Mechanism of action

Methyldopa has a dual mechanism of action:

Pharmacokinetics

Methyldopa exhibits variable absorption from the gastrointestinal tract. It is metabolized in the liver and intestines and is excreted in urine.

History

When methyldopa was first introduced, it was the mainstay of antihypertensive treatment, but its use has declined on account of relatively severe adverse side effects, with increased use of other safer and more tolerable agents such as alpha blockersbeta blockers, and calcium channel blockers. Additionally, it has yet to be associated with reducing adverse cardiovascular events including myocardial infarction and stroke, or overall all-cause mortality reduction in clinical trials.[8] Nonetheless, one of methyldopa’s still current indications is in the management of pregnancy-induced hypertension (PIH), as it is relatively safe in pregnancy compared to many other antihypertensives which may affect the fetus.

PATENT

https://patents.google.com/patent/CN105693541B/en

 L-methyldopa an α2 receptor agonistic cardiovascular drugs. The structural formula is as follows:

[0003]

Figure CN105693541BD00031

[0004] The product produced methyl α- demethylated metabolite of norepinephrine, blockade of central α receptor, thereby inhibiting the heart, kidney and peripheral vascular sympathetic drive output at the same time, peripheral vascular resistance in vivo and plasma renin activity is reduced, and thus decrease blood pressure. It can be used for treating hypertension, nephropathy, including hypertension time.This product is safe, is the preferred treatment during pregnancy with hypertension drugs.

[0005] In the prior art, methyldopa synthesis are the following:

[0006] 1 to veratridine-one was synthesized by the synthesis of L-hydantoin intermediate methyldopa:

[0007]

Figure CN105693541BD00032

[0008] 2 to veratridine-one was synthesized by the synthesis of L-amino nitrile intermediate methyldopa:

[0009]

Figure CN105693541BD00033

[0010] 3, eugenol synthesized from L-methyldopa

[0011]

Figure CN105693541BD00041

[0012] The plurality of reaction have their own advantages, but in general, the reaction need to use highly toxic cyanide, have a certain impact on the environment and operating conditions.

SUMMARY

[0013] The present invention discloses a method for synthesizing methyldopa, the synthetic route without using highly toxic substances, the advantage of having a clean environment and efficient.

[00 M] methyldopa synthesis method disclosed in the present invention, is 3,4-dimethoxybenzaldehyde with 2-acetylamino-propionic acid methyl ester as a starting material synthesized by condensation, reduction, deprotection to give the crude product methyldopa, methyldopa and then purified to give pure product.Scheme with easy operation, high yield, etc. cleaning process.

[0015] The scheme is as follows:

[0016]

Figure CN105693541BD00042

Example 1

[0034] (A) Weigh 3,4_-dimethoxybenzaldehyde 16.6g (0. Imol), sodium methoxide 5.4g (0. Imol), into dried dimethylformamide (150ml), stirring dissolution was complete, the reactor was placed in a cold water bath controlled at a temperature of about 20 ° C, weighed 2-acetamido-methyl 14.5g (0. Imol), successively portionwise added to the reactor, the reaction was stirred for at least 5 minutes plus complete. After all was added, maintaining the reaction temperature for 1.5h.After completion of the reaction, cold water was added Intermediate precipitated solid was filtered and washed several times with cold water.

[0035] (B) Intermediate (A) obtained was transferred to the reactor, 150ml of dichloromethane was added to dissolve, was added p-toluenesulfonyl chloride 19. Ig (0. Imol), triethylamine reactor after 10. Ig (0. Imol), the reaction was stirred for 2h, sodium boron hydride was added 4g, reaction was continued for lh. After completion of the reaction, cold water was added and sufficiently stirred, the aqueous layer was discarded liquid separation, the organic layer, the solvent was evaporated under reduced pressure to obtain an intermediate;

[0036] (C) Intermediate (B) obtained was transferred to the reactor was added 150ml 47% aqueous hydrobromic acid to the reactor, warmed to about 60 ° C, the reaction was stirred at reflux for 4h. Hydrobromic acid was distilled off under reduced pressure to about IlOml, filtered, the mother liquor was concentrated to dryness under reduced pressure, dissolve the solid with cold water, and ammonia to adjust the pH to 4.5 with a cold water bath, the precipitated white solid was large. Filtered and the solid washed with a little cold methylene chloride to give 20.8 g of crude product methyldopa, yield 98.5%.

[0037] (D) The crude product take methyldopa, add 30ml 0. Imo 1 / L dilute hydrochloric acid, an Ig activated carbon, heated, stirred until dissolution methyldopa, maintaining the temperature 〇.5h, filtered hot and allowed to cool to ammonia to adjust the pH to 4.5 to precipitate large amount of white solid was filtered, rinsed with a small amount of cold water, and dried to give 17.7 g methyldopa pure, a yield of 85.0%. Content was determined according to the “Chinese Pharmacopoeia” method and its content was 99.6%.

[0038] Example 2

[0039] (A) Weigh 166kg of 3,4-dimethoxybenzaldehyde, 54kg sodium methoxide, into dried dimethylformamide 500L stirred to dissolve completely, the reactor was placed in a cold water bath controlled temperature of about 20 ° C, 2-acetamido-Weigh 145kg methyl, successively portionwise added to the reactor, the reaction was stirred for at least 5 minutes the addition was completed. After all was added, maintaining the reaction temperature for 2 h. After completion of the reaction, cold water was added Intermediate precipitated solid was filtered and washed several times with cold water.

[0040] (B) Intermediate (A) obtained was transferred to the reactor, 500L of methylene chloride was added to dissolve, was added p-toluenesulfonyl chloride 19Ikg, triethylamine 10Ikg into the reactor, the reaction was stirred for 2.5h , sodium borohydride was added 4kg, reaction was continued for 1.3h. After completion of the reaction, cold water was added and sufficiently stirred, the aqueous layer was discarded liquid separation, the organic layer, the solvent was evaporated under reduced pressure to obtain an intermediate;

[0041] (C) Intermediate (B) obtained was transferred to the reactor, was added 500L 47% aqueous hydrobromic acid to the reactor, warmed to about 60 ° C, the reaction was stirred at reflux for 4h. Hydrobromic acid was distilled off under reduced pressure to about 375L, filtered, and the mother liquor was concentrated to dryness under reduced pressure, dissolve the solid with cold water, and ammonia to adjust the pH to 4.5 with a cold water bath, the precipitated white solid was large. Centrifuged, and the solid washed with a little cold water to give the crude product methyldopa 200kg, 94.7% yield.

[0042] (D) The crude product take methyldopa, add 300L O.lmol / L dilute hydrochloric acid, 10 kg activated carbon, heating and stirring until dissolved methyldopa, maintaining the temperature 〇.5h, filtered hot and allowed to cool to ammonia to adjust the pH to 4.5 to precipitate large amount of white solid was filtered, rinsed with a small amount of cold water, and dried to give pure methyldopa 177kg, 88.5% yield. Content was determined according to the “Chinese Pharmacopoeia” method and its content was 99.7%.

CLIP

File:Methyldopa synthesis.svg

Exists as the sesquihydrate.

Prepn: Pfister, Stein, US 2868818 (1959 to Merck & Co.). D. F. Reinhold and M. Sletzinger, GB 936074 eidem U.S. Patent 3,344,023 (1963 to Merck and Co.)

Resolution: Jones et al., US 3158648 (1964 to Merck & Co.); cf. Slates et al., J. Org. Chem. 29, 1424 (1964). Resolution and configuration: Tristram, ibid. 2053.

Synthesis from asymmetric intermediates: Reinhold et al., J. Org. Chem. 33, 1209 (1968).

Prepn of the ethyl ester hydrochloride: FR M2153 (1963 to Merck & Co.);

of pharmaceutical dosage forms: Marcus, US 3230143 (1966 to Merck & Co.).

CLIP

Reactions of D-glucose with phenolic amino acids: further insights into the competition between Maillard and Pictet-Spengler condensation pathways
Carbohydrate Research (2005), 340, (18), 2719-2727

Methyldopa

    • ATC:C02AB01
  • Use:antihypertensive
  • Chemical name:3-hydroxy-α-methyl-l-tyrosine
  • Formula:C10H13NO4
  • MW:211.22 g/mol
  • CAS-RN:555-30-6
  • InChI Key:CJCSPKMFHVPWAR-JTQLQIEISA-N
  • InChI:InChI=1S/C10H13NO4/c1-10(11,9(14)15)5-6-2-3-7(12)8(13)4-6/h2-4,12-13H,5,11H2,1H3,(H,14,15)/t10-/m0/s1
  • EINECS:209-089-2

Synthesis

References

    •  Tristram, E.W. et al.: J. Org. Chem. (JOCEAH) 29, 2053 (1964).
    • B Stein, G.A. et al.: J. Am. Chem. Soc. (JACSAT) 77, 700 (1955).
    •  Chem. Eng. from 8.11.1965; p. 247.
    • C Reinhold, D.F. et al.: J. Org. Chem. (JOCEAH) 33, 1209 (1968).
    • A US 2 868 818 (Merck & Co.; 13.1.1959; prior. 15.12.1953).
    •  GB 936 074 (Merck & Co.; appl. 18.10.1960; USA-prior. 8.4.1960, 24.8.1960).
    •  DE 1 171 931 (Merck & Co.; prior. 6.10.1960).
    •  US 3 158 648 (Merck & Co.; 24.11.1964; prior. 11.7.1961, 9.4.1962).
    •  FR 1 492 765 (Merck & Co.; appl. 10.10.1963; USA-prior. 11.10.1962, 19.9.1963).
  • similar method via l-α-acetylamino-α-vanillylpropionitrile:

    • GB 1 142 595 (Merck & Co.; appl. 23.5.1967, 12.2.1969).
  • alternative syntheses:

    • D a Steinetal, G.A.: J. Am. Chem. Soc. (JACSAT) 77, 700 (1955).
    • US 3 366 679 (Merck & Co.; 30.1.1968; prior. 11.10.1962, 19.9.1963).
    • DOS 2 302 937 (Tanabe; appl. 22.1.1973; J-prior. 22.1.1972).
    • US 3 517 057 (Merck & Co.; 23.6.1970; appl. 21.9.1967).
    • DE 1 235 946 (Boehringer Mannh.; appl. 8.8.1964).
    • DE 1 235 947 (Bayer; appl. 16.1.1963).
    • DE 1 258 416 (Knoll; appl. 9.10.1964).
    • DE 1 269 622 (Knoll; appl. 22.12.1966).
    • DOS 2 406 898 (BASF; appl. 14.2.1974).
    • AT 250 936 (Egyesült; appl. 3.11.1964; HU-prior. 18.11.1963).
    • FR 1 502 972 (Merck & Co.; appl. 21.10.1966; USA-prior. 22.10.1965).
    • FR 1 531 877 (Sankyo; appl. 18.7.1967; J-prior. 11.8.1966, 21.2.1967).
    • GB 1 321 802 (D.D.S.A.; appl. 5.2.1971).
    • b GB 2 059 955 (Merck & Co.; appl. 9.9.1980; USA-prior. 13.9.1979, 28.9.1979).
Methyldopa
Skeletal formula of methyldopa
Ball-and-stick model of the methyldopa molecule
Clinical data
Trade names Aldomet, Aldoril, Dopamet, others
Synonyms L-α-Methyl-3,4-dihydroxyphenylalanine
AHFS/Drugs.com Monograph
MedlinePlus a682242
Pregnancy
category
  • AU: A
  • US: B (No risk in non-human studies)
Routes of
administration
by mouth, IV
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability approximately 50%
Metabolism Liver
Onset of action 4 to 6 hrs[1]
Elimination half-life 105 minutes
Duration of action 10 to 48 hrs[1]
Excretion Kidney for metabolites
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.008.264 Edit this at Wikidata
Chemical and physical data
Formula C10H13NO4
Molar mass 211.215 g/mol g·mol−1
3D model (JSmol)

Other Names

  • Alanine, 3-(3,4-dihydroxyphenyl)-2-methyl-, L- (8CI)
  • 3-Hydroxy-α-methyl-L-tyrosine
  • (-)-Methyldopa
  • (-)-α-Methyl-3,4-dihydroxyphenylalanine
  • (-)-α-Methyldopa
  • (2S)-2-Amino-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid
  • (S)-(-)-α-Methyldopa
  • (S)-α-Methyldopa
  • 2-Methyl-3-(3,4-dihydroxyphenyl)alanine
  • AMD
  • Aldochlor
  • Aldomet
  • Aldometil
  • Aldomin
  • Aldomine
  • Alpha medopa
  • Alphamethyldopa
  • Bayer 1440L
  • Baypresol
  • Dopamet
  • Dopatec
  • Dopegyt
  • Elanpres
  • Equibar
  • L-(-)-α-Methyl-β-(3,4-dihydroxyphenyl)alanine
  • L-(-)-β-(3,4-Dihydroxyphenyl)-α-methylalanine
  • L-2-Amino-2-methyl-3-(3,4-dihydroxyphenyl)propionic acid
  • L-3,4-Dihydroxy-α-methylphenylalanine
  • L-3,4-Dihydroxyphenyl-2-methylalanine
  • L-Methyldopa
  • L-α-Methyl-3,4-dihydroxyphenylalanine
  • L-α-Methyl-3-(3,4)-dihydroxyphenylalanine
  • L-α-Methyldopa
  • Lederdopa
  • Levo-3-(3,4-Dihydroxyphenyl)-2-methylalanine
  • MK 351
  • Medomet
  • Medopa
  • Medopren
  • Methoplain
  • Methyl-L-dopa
  • Methyldopa
  • NSC 169916
  • Nr.C 2294
  • Presinol
  • Presolisin
  • Sembrina
  • l-3-(3,4-Dihydroxyphenyl)-2-methylalanine
  • l-α-Methyldopa
  • α-Methyl-L-3,4-dihydroxyphenylalanine
  • α-Methyl-L-dopa
  • α-Methyldopa

General References

  1. Djamshidian A, Poewe W: Apomorphine and levodopa in Parkinson’s disease: Two revolutionary drugs from the 1950’s. Parkinsonism Relat Disord. 2016 Dec;33 Suppl 1:S9-S12. doi: 10.1016/j.parkreldis.2016.12.004. Epub 2016 Dec 22. [PubMed:28012951]
  2. Meiser J, Weindl D, Hiller K: Complexity of dopamine metabolism. Cell Commun Signal. 2013 May 17;11(1):34. doi: 10.1186/1478-811X-11-34. [PubMed:23683503]
  3. Elroby SA, Makki MS, Sobahi TR, Hilal RH: Toward the understanding of the metabolism of levodopa I. DFT investigation of the equilibrium geometries, acid-base properties and levodopa-water complexes. Int J Mol Sci. 2012;13(4):4321-39. doi: 10.3390/ijms13044321. Epub 2012 Apr 2. [PubMed:22605980]
  4. Robertson DR, Wood ND, Everest H, Monks K, Waller DG, Renwick AG, George CF: The effect of age on the pharmacokinetics of levodopa administered alone and in the presence of carbidopa. Br J Clin Pharmacol. 1989 Jul;28(1):61-9. [PubMed:2775615]
  5. Abrams WB, Coutinho CB, Leon AS, Spiegel HE: Absorption and metabolism of levodopa. JAMA. 1971 Dec 27;218(13):1912-4. [PubMed:5171067]
  6. Fanali G, Rampoldi V, di Masi A, Bolli A, Lopiano L, Ascenzi P, Fasano M: Binding of anti-Parkinson’s disease drugs to human serum albumin is allosterically modulated. IUBMB Life. 2010 May;62(5):371-6. doi: 10.1002/iub.317. [PubMed:20225277]
  7. FDA Approved Drug Products: Sinemet [Link]
  8. Sinemet FDA Label [File]

/////////Methyl-L-dopa, Methyldopa, NSC 169916

N[C@@H](CC1=CC(O)=C(O)C=C1)C(O)=O

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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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