D(-)-4-Hydroxyphenylglycine Market Research

Brief introduction to D(-)-4-Hydroxyphenylglycine


D(-)-4-Hydroxyphenylglycine (D-p-HPG or DHPG for short) is an important pharmaceutical intermediate. D(-)-4-Hydroxyphenylglycine and its highly processed product PH Dane salt is the necessary side chain intermediate for the synthesis of highly efficient broad-spectrum antibacterial drugs. Derivatives of D(-)-4-Hydroxyphenylglycine such as D-P-Hydroxy-phenylglycine methyl ester, (R)-Amino-(4-hydroxyphenyl)acetic acid methyl ester hydrochloride, or D-(-)-A-4-Hydroxyphenylglycine Dane Salt Methyl Potassium (CAS#: 69416-61-1), are all synthesized with D(-)-4-Hydroxyphenylglycine as the raw material.

Physic-chemical properties of D(-)-4-Hydroxyphenylglycine

Product name: D(-)-4-Hydroxyphenylglycine
CAS No.: 22818-40-2
Synonym: D-P-Hydroxyphenylglycine; D-HPG
Molecular formula: C8H9NO3
Molecular weight: 167.16
Appearance: White or off-white crystalline powder
Purity: ≥98.5% (>99% for medical grade)
Melting point: 240 °C (dec.)(lit.)
Specific rotation: -156 º (c=1, 1 N HCl)
Density: 1.396
Refractive rate: -158 ° (C=1, 1mol/L HCl)
Solubility: 5 g/L (20 ºC)

Applications of D(-)-4-Hydroxyphenylglycine

D-(-)-A-4-Hydroxyphenylglycine Dane Salt Methyl Potassium is a semi-synthetic antibiotic API. It is mainly used as the side chain compound for semi-synthetic β-lactam antibiotics, i.e. Pharmaceutical intermediate for semi-synthetic penicilin and cephalosporin. Medicines produced from D-(-)-A-4-Hydroxyphenylglycine Dane Salt Methyl Potassium include Amoxicillin, Amoxicillin clavulanate, Cefadroxil, cephalosporin, etc. Among them, Amoxicillin and its Clavulanic acid compound preparation are the largest consumers of D(-)-4-Hydroxyphenylglycine.

Compared to the traditional antibiotics such as pennicillin and ampicillin, besides the anti-gram positive bacteria effect, Amoxicillin has the anti-gram negative bacteria effect, too. Moreover, Amoxicillin is stable and not easily broken by gastric acid. It also has broad anti-bacteria spectrum. With little side effect, Amoxicillin is effective to be taken orally. As a medicine recommended by WHO, Amoxicillin is in larger and larger demand all over the world. This trend in turn drives the development of the D(-)-4-Hydroxyphenylglycine market.

D(-)-4-Hydroxyphenylglycine reacting with Potassium hydroxide and Sodium hydroxide would yield Dane Salt Methyl Potassium and Sodium Dane Salt respectively. The latter is the significant side chain compound to synthesize semi-synthetic Amoxicillin and cephalosporin antibiotics Cefadroxil, Cefoperazone, and so on. D(-)-4-Hydroxyphenylglycine can be applied to produce Cefprozil, Cefatrizine, etc. Due to the multiple applications and its subjection to both injection and oral taking, D(-)-4-Hydroxyphenylglycine excels Ampicillin clinically.

Main specifications of D(-)-4-Hydroxyphenylglycine

There seems to be no national standards for D(-)-4-Hydroxyphenylglycine, while there are national standards for D-(-)-A-4-Hydroxyphenylglycine Dane Salt Methyl Potassium, which was drafted by Chemical Industry Association in 2007, as below:






White or off-white crystalline powder





Specific rotation[α]D20



Sulfate (SO24)



Chloride (C1)

0.03 % 


Heavy metal (pb)

15 mg/kg





Loss on drying



Color of solvent, A 


Standards of D-(-)-A-4-Hydroxyphenylglycine Dane Salt Methyl Potassium

HG/T 3936-2007-D-(-)-A-4-Hydroxyphenylglycine Dane Salt Methyl Potassium content summary: requirements, test method and rules, symbol, package, transportation and storage.

This standard applies to the production, test, and sales of the D-(-)-A-4-Hydroxyphenylglycine Dane Salt Methyl Potassium synthesized from D(-)-4-Hydroxyphenylglycine and Methyl acetoacetate. The product is mainly applied in the synthesis of beta-lactam antibiotics such as Amoxicillin and cefadroxil penicillin. Technical index of D-(-)-A-4-Hydroxyphenylglycine Dane Salt Methyl Potassium are as below:






White or off-white crystalline powder


Mass fraction (%)



Specific rotation [α]D20



Loss on drying (%  )



PH Value (50g/L solvent)



Absorbance (50g/L solvent) 



Free D(-)-4-Hydroxyphenylglycine % 


Development of D(-)-4-Hydroxyphenylglycine

Research on the synthesis of D(-)-4-Hydroxyphenylglycine abroad started from 1960s ~1970s. Since 1970s, there were bulk production of the product, and the production was developed further between 1980s and 1990s. Demand for D(-)-4-Hydroxyphenylglycine increases fast in recent years. According to reports, in 1999, for the production of Amoxicillin alone, the demands for D(-)-4-Hydroxyphenylglycine in the US., Europe, and Japan exceeded 10,000 MT, and demands in the rest of the world was as large as 8000 MT. Manufacturers of D(-)-4-Hydroxyphenylglycine globally include the Japanese companies Nippon Gohsei and HIGH CHEM, the Holland companies ANDN and DSM, Derivados of Spain, Champhor of Taiwan, and other companies in Korea and Sweden.

In China, research of D(-)-4-Hydroxyphenylglycine started from 1980, and production in small scale started from mid-1990s. Recently, the demand for Amoxicillin in China increases rapidly. Quite some antibiotic manufacturers passed pilot experiments of semi-synthetic antibiotics and cephalosporins one after another and shifted to bulk production.

Research and development of D(-)-4-Hydroxyphenylglycine started early in China, but the production process was limited to chemical methods. Currently, many factories in Shanghai, Zhejiang, Jiangsu, and Hebei are producing D(-)-4-Hydroxyphenylglycine with chemical methods. However, the products therefrom fail to compete with the imported products produced by enzyme method due to the long process, low yield, high cost, and bad quality.

Through decades of development, there has been relatively stable market structure for D(-)-4-Hydroxyphenylglycine. From 2007 on, because a number of D(-)-4-Hydroxyphenylglycine projects started in China, and there was a great cost advantage, manufacturers abroad gradually reduced the production size of the product and transferred it to China. So far the yield of D(-)-4-Hydroxyphenylglycine in China takes up over 75% of the total yield globally.

Upstream raw materials of D(-)-4-Hydroxyphenylglycine

The upstream raw materials of D(-)-4-Hydroxyphenylglycine mainly include Phenol, D(-)-Tartaric acid, Glyoxal, etc.

Downstream products of D(-)-4-Hydroxyphenylglycine

As an important side chain compound, D(-)-4-Hydroxyphenylglycine reacts with 6-APA and 7-ADCA to synthesize antibiotics.

Presently, antibiotics synthesized from D(-)-4-Hydroxyphenylglycine and its salts include Amoxicillin, Cefadroxil, Cefatrozine, Cefoperazone, Cefpiramide Sodium, Aspoxillin, and so on.

The downstream industry of D(-)-4-Hydroxyphenylglycine focuses on the production of antibiotic APIs such as Amoxicillin, Cefoperazone, and Cefadroxil.

1. Brief introduction to Amoxicillin

Internationally, Amoxicillin has been key medicine since 1960s. In 1970s, it came to the heyday of its development. In China, trial production of Amoxicillin started in 1976, and regular production started in 1979. Annual yield of Amoxicillin in 1979 was only 320KG, and the raw material 6-APA was all imported.

As one of the broadly applied orally taken penicillin, the preparation of Amoxicillin covers capsules, pills, granules, dispersible tablet, etc. Amoxicillin continues to take lead in the semi-synthetic penicillin products at the beginning of 21st century and keeps the rising trend.

Nowadays, Amoxicillin is one of the most highly competitive pharmaceutical product in the market. There are a large number of manufacturers, counting more than 100. At present market of the product has been mature. In the fierce competitions, manufacturers of large yields continue to expand and the market concentration has been increasing. So far the market is dominated by Harbin Pharmaceutical Group Holding Co. and CSPC Pharmaceutical Group Limited. In 2006, capacity of Amoxicillin API in China reached 15,000 MT, with the year-on-year growth of around 25%. Among them, the annual capacity of CSPC Pharmaceutical Group Limited, North China Pharmaceutical Company, and United Laboratories has all exceeds 3000 MT, and some of them even exceed 4000 MT.

According to foreign media, the global Amoxicillin API total yield was around 20,000 MT in 2006. By the end of 2015, the number was almost doubled, revealing the tremendous demand for Amoxicillin from the international market.

2. Cephalosporin

To date, there are 56 variety of Cephalosporin in the globally market, covering generations I to IV.

Cephalosporin takes up a large ratio of the global anti-infective drugs market. Its current sales volume takes up 40% of the total sales volume of the anti-infective drugs, and in some countries, the ratio is higher than this. In the US market, the sales volume of Cephalosporin takes up 45% of the total sales volume of the anti-infective drugs.

The Cephalosporin industry is characterized for high technological content, high investment quota, and high risk. The R & D cost of Cephalosporin by Novartis, Glaxo, and Roche has all exceeds 1.8 billion US dollars, and their sales volumes take up 18%, 13%, and 20%, respectively, of the total sales volume of the drug.

Price of D(-)-4-Hydroxyphenylglycine

In 2017, with the rise in price of the upstream raw materials and the increase of environmental protection pressures, prices of the Amoxicillin side chain products rise, too. It is the same case with (R)-Amino-(4-hydroxyphenyl)acetic acid methyl ester hydrochloride.

There were large differences between the historic prices of D(-)-4-Hydroxyphenylglycine. Therefore, for the specific price at this point, please refer to phone-call consultation.

Mainstream production process of D(-)-4-Hydroxyphenylglycine

Production methods of D(-)-4-Hydroxyphenylglycine are divided into chemical resolution and enzyme method. They can be further divided into 3 classifications, namely, chemical synthetic resolution, one enzyme and one acid in 2 steps, and two bacteria and two enzymes in 1 step. Please see below for the specific steps.

Method Ⅰ: Chemical synthetic resolution Synthesize

DL-P-Hydroxyphenylglycine by Anisic aldehyde - Sodium cyanide, Strecker amino acid synthesis, glyoxalic acid - urea - phenol, aminolysis of 4-Hydroxyphenylglycolic acid, or glyoxylic acid - ammonium salt coupling. Get D(-)-4-Hydroxyphenylglycine by chemical resolution or induced crystallization. 4-Hydroxy-L-phenylglycine should be racemized and repeatedly resolved.

Synthesize racemic DL- HPG first, and then get D(-)-4-Hydroxyphenylglycine by chemical or biological resolution. There is no natural product of D(-)-4-Hydroxyphenylglycine. It can only yield from artificial synthesis.

Synthesize DL-P-Hydroxyphenylglycine from glyoxylic acid, phenol and active amido. Esterify DL-P-Hydroxyphenylglycine with methanol, resolve it with D(-)-Tartaric acid, and get D(-)-4-Hydroxyphenylglycine. Around 2008, most D(-)-4-Hydroxyphenylglycine manufacturers in China relied on the glyoxylic acid method.

1. Anisic aldehyde - Sodium cyanide method

With this method, Anisic aldehyde and Sodium cyanide are applied to water or organic solvent. Heat it to condense to 4-Hydroxyphenyl hydantoin. Then compress and hydrolyze it under alkaline conditions and get D(-)-4-Hydroxyphenylglycine. This method has been eliminated though due to the long reaction process, low yield, and high cost.

2. Strecker amino acid synthesis

After condensation of p-Hydroxybenzaldehyde and sodium cyanide, hydrolyze the product in acid solution and get D(-)-4-Hydroxyphenylglycine. This process is mature and simple. Reacting time is short and the quantity of waster water is small. The yield is as high as 70%. However, the expensive raw material p-Hydroxybenzaldehyde and the highly toxic sodium cyanide are involved, so the cost is high.

3. Glyoxalic acid - urea - phenol method

Glyoxalic acid, urea and phenol react and yield 5-(4-Hydroxyphenyl)- 2,4-imidazolidinedione. Compress and hydrolyze it under alkaline conditions and get D(-)-4-Hydroxyphenylglycine. With this method, raw material is easy to get, and there are few reacting steps. However, the reaction time is as long as 30 hours, and the yield is not high, so few manufacturers adopt it.

4. 4-Hydroxyphenylglycolic acid aminolysis

4-Hydroxyphenylglycolic acid reacts with acetic anhydride, then get D(-)-4-Hydroxyphenylglycine by aminolysis. The yield is as high as 90%. With this method, handling is simple and yield is high, but the reaction time is longer than 20 hours. Now the process has been improved and the reaction time is reduced to 8 hours, so it is good for industrialization.

5. Glyoxylic acid-phenol-ammonium salt one-step synthesis

This method is newly developed and general in use. Glyoxylic acid, phenol, and ammonium salt react in one step to get DL-P-Hydroxyphenylglycine. Split it with enzyme method and get D(-)-4-Hydroxyphenylglycine.

With this method, raw materials are readily available and the cost is low. However, the reacting time is long, and yield is as low as 40%. The highest yield is only 53.9%. Now this method has been successfully improved. Replace ammonium acetate with sulfamic acid, the yield reaches 60%, and the fractional conversion of glyoxylic acid, phenol, and sulfamic acid is higher than 90%. Post-treatment is easy to handle. Adding proper catalyzer, the reacting time is reduced to 12 hours. This method is very competitive.

Method Ⅱ: One enzyme and one acid in two steps

This was a method popular at the early stage of the development of D(-)-4-Hydroxyphenylglycine production. Use hydantoin hydrolase to hydrolyze 4-Hydroxyphenyl hydantoin to an intermediate product, cool it to 0℃, and hydrolyze it with nitrous acid and get the end product. Because of the involvement of nitrous acid, the production cost is high, and there will be negative effect on the environment and the product quality.

Method Ⅲ: Two bacteria and two enzyme in one step

This is the predominant method adopted internationally presently. Hydrolyze 4-Hydroxyphenyl hydantoin with hydantoin hydrolase and 5-Iodo-2'-deoxycytidine which are produced from strain to extract D(-)-4-Hydroxyphenylglycine. Characteristics of this method include inducer initiated by genes and synthesized in clean production, bacteria collected with composite flocculant, so cells do not break and enzyme activity is not reduced.

Production process

Chemical synthesis and resolution

One enzyme and one acid in two steps

Two bacteria and two enzyme in one step

Pro and con

Mature but long process, complicated handling, heavy pollution, and high cost.

Mature but long process, involvement of nitrous acid, and high cost.

Short process, easy handling, and low cost.

Developing trend

Used at the early stage and eliminated by foreign manufacturers, but popular with Chinese manufacturers.

Currently popular globally.

The most advanced production process at present.

Development of D(-)-4-Hydroxyphenylglycine resolution technologies

It is the l-isomer of D(-)-4-Hydroxyphenylglycine that is mostly in use. So it is an important job to split the product. However, because d-isomer and l-isomer are identical in physical properties in non-chiral environment, it is difficult to split them. The process will be very long, the yield is low, problems with waste gas, waste water, and industrial residue are serious, and quality index including optical purity and clarity are relatively bad. Therefore, this method has been eliminated by foreign countries, however, most manufacturers in China are still producing in this method. The production yield is low.

There are several ways to split d-isomer and l-isomer, as stated below:

1. Chemical resolution

It is a broadly-applicated method. React D(-)-4-Hydroxyphenylglycine with optical active agent and yield diastereoisomer. Split it basing on the difference in physical properties. The frequently-used resolution agents include D(-)-Tartaric acid, bromo camphor sulfonic acid, benzenesulfonic acid, etc. With this method, the reacting process is long, with only approximately 50% yield. The key is to choose the proper resolution agent for long operating cycle and easy recycling.

2. Induced crystallization

Basing on the physical properties of amino compound, add an optical isomer to the raceme solvent as inoculating crystal to induce the precipitation of the isomer identical to the inoculating crystal, and realize resolution. Firstly, prepare oversaturated solution of raceme, and then add d-isomer or l-isomer inoculating crystal. With this process, cost is largely reduced. It is worth vigorous promotion.

3. Biological resolution

This is a way for resolution that is greatly proposed. It is in broad application abroad, and China should follow the trend. This method is most economic and apt for bulk production, with promising prospective.

D(-)-4-Hydroxyphenylglycine manufacturers

Banff Green Technologies, Inc. is a professional D(-)-4-Hydroxyphenylglycine manufacturer in China. The annual capacity and yield are thousands of tons.

We adopt the most advanced D(-)-4-Hydroxyphenylglycine production process, which is environment friendly. Our full automationalized production is characterized with nice production environment, high product quality, low cost, reliability and broad developing prospective.

Should you need the info regarding price, COA, MSDS, specifications, and technologies of our D(-)-4-Hydroxyphenylglycine, please do not hesitate to contact us directly.